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  • 1.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Rahl, Karin
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    Phenotypes of myopathy-related beta-tropomyosin mutants in human and mouse tissue cultures2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 9, article id e72396Article in journal (Refereed)
    Abstract [en]

    Mutations in TPM2 result in a variety of myopathies characterised by variable clinical and morphological features. We used human and mouse cultured cells to study the effects of β-TM mutants. The mutants induced a range of phenotypes in human myoblasts, which generally changed upon differentiation to myotubes. Human myotubes transfected with the E41K-β-TM(EGFP) mutant showed perinuclear aggregates. The G53ins-β-TM(EGFP) mutant tended to accumulate in myoblasts but was incorporated into filamentous structures of myotubes. The K49del-β-TM(EGFP) and E122K-β-TM(EGFP) mutants induced the formation of rod-like structures in human cells. The N202K-β-TM(EGFP) mutant failed to integrate into thin filaments and formed accumulations in myotubes. The accumulation of mutant β-TM(EGFP) in the perinuclear and peripheral areas of the cells was the striking feature in C2C12. We demonstrated that human tissue culture is a suitable system for studying the early stages of altered myofibrilogenesis and morphological changes linked to myopathy-related β-TM mutants. In addition, the histopathological phenotype associated with expression of the various mutant proteins depends on the cell type and varies with the maturation of the muscle cell. Further, the phenotype is a combinatorial effect of the specific amino acid change and the temporal expression of the mutant protein.

  • 2.
    Abdul-Hussein, Saba
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Expression profiles of muscle disease-associated genes and their isoforms during differentiation of cultured human skeletal muscle cells2012In: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 13, article id 262Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The formation of contractile myofibrils requires the stepwise onset of expression of muscle specific proteins. It is likely that elucidation of the expression patterns of muscle-specific sarcomeric proteins is important to understand muscle disorders originating from defects in contractile sarcomeric proteins.

    METHODS: We investigated the expression profile of a panel of sarcomeric components with a focus on proteins associated with a group of congenital disorders. The analyses were performed in cultured human skeletal muscle cells during myoblast proliferation and myotube development.

    RESULTS: Our culture technique resulted in the development of striated myotubes and the expression of adult isoforms of the sarcomeric proteins, such as fast TnI, fast TnT, adult fast and slow MyHC isoforms and predominantly skeletal muscle rather than cardiac actin. Many proteins involved in muscle diseases, such as beta tropomyosin, slow TnI, slow MyBPC and cardiac TnI were readily detected in the initial stages of muscle cell differentiation, suggesting the possibility of an early role for these proteins as constituent of the developing contractile apparatus during myofibrillogenesis. This suggests that in disease conditions the mechanisms of pathogenesis for each of the mutated sarcomeric proteins might be reflected by altered expression patterns, and disturbed assembly of cytoskeletal, myofibrillar structures and muscle development.

    CONCLUSIONS: In conclusion, we here confirm that cell cultures of human skeletal muscle are an appropriate tool to study developmental stages of myofibrillogenesis. The expression of several disease-associated proteins indicates that they might be a useful model system for studying the pathogenesis of muscle diseases caused by defects in specific sarcomeric constituents.

  • 3.
    Calame, Daniel G.
    et al.
    Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA ; Texas Children’s Hospital, Houston, TX, USA.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Lupski, James R.
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA ; Texas Children’s Hospital, Houston, TX, USA ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA ; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
    Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia2022In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, no 2, p. 304-321Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683).

    METHODS: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed.

    RESULTS: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism.

    INTERPRETATION: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022.

  • 4.
    Chatron, Nicolas
    et al.
    Genetics Department, Lyon University Hospital, France / Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    Becker, Felicitas
    Department of Neurology, University of Ulm, Germany / University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Germany.
    Morsy, Heba
    Human Genetics Department, Medical Research Institute, Alexandria University, Egypt.
    Schmidts, Miriam
    Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen, The Netherlands / Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands / Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Germany.
    Hardies, Katia
    Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Belgium.
    Tuysuz, Beyhan
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Roselli, Sandra
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Najafi, Maryam
    Genome Research Division, Human Genetics Department, Radboud University Medical Center Nijmegen, The Netherlands / Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
    Alkaya, Dilek Uludag
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Ashrafzadeh, Farah
    Department of Paediatric Neurology, Ghaem Medical Centre, School of Medicine, Mashhad University of Medical Sciences, Iran.
    Nabil, Amira
    Human Genetics Department, Medical Research Institute, Alexandria University, Egypt.
    Omar, Tarek
    Pediatrics Department, Faculty of Medicine, Alexandria University, Egypt.
    Maroofian, Reza
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London, UK.
    Karimiani, Ehsan Ghayoor
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s, University of London, UK / Innovative medical research center, Mashhad branch, Islamic Azad University, Mashhad, Iran.
    Hussien, Haytham
    Pediatrics Department, Faculty of Medicine, Alexandria University, Egypt.
    Kok, Fernando
    Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, SP, Brazil.
    Ramos, Luiza
    Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, SP, Brazil.
    Gunes, Nilay
    Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Medical Faculty, Turkey.
    Bilguvar, Kaya
    Department of Genetics, Yale Center for Genome Analysis (YCGA), Yale University, School of Medicine, New Haven, Connecticut.
    Labalme, Audrey
    Genetics Department, Lyon University Hospital, France.
    Alix, Eudeline
    Genetics Department, Lyon University Hospital, France.
    Sanlaville, Damien
    Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    de Bellescize, Julitta
    Department of Pediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, ERN EpiCARE, University Hospitals of Lyon, France.
    Poulat, Anne-Lise
    Department of Pediatric Neurology, Lyon University Hospital, Lyon, France.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Lerche, Holger
    University of Tübingen, Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, Germany.
    May, Patrick
    Luxemburg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg.
    Lesca, Gaetan
    Genetics Department, Lyon University Hospital, France / Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 Université de Lyon, Université Claude Bernard Lyon 1, France.
    Weckhuysen, Sarah
    Neurogenetics Group, VIB-Center for Molecular Neurology, University of Antwerp, Belgium / Department of Neurology, University Hospital Antwerp, Belgium.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy2020In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 143, no 5, p. 1447-1461Article in journal (Refereed)
    Abstract [en]

    Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.

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  • 5.
    Cuisset, J. M.
    et al.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Maurage, C. A.
    Service d'Anatomie Pathologique, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    Pellissier, J. F.
    Laboratoire de Biopathologie Neuromusculaire, JE 2053, Centre hospitalier universitaire et faculté de médecine de La Timone, Marseille, France.
    Barois, A.
    Service de réanimation pédiatrique, Hôpital Raymond-Poincaré, Garches, France.
    Urtizberea, J. A.
    Institut de Myologie, Hôpital Pitié-Salpétrière, Paris, France.
    Laing, N.
    Center for neuromuscular and neurological disorders, Australian neuromuscular research institute, University of Western Australia, Nedlands, WA, Australia.
    Tajsharghi, H
    Department of pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Vallée, L.
    Service de Neuropédiatrie, Centre hospitalier régional universitaire et faculté de médecine, Lille, France.
    'Cap myopathy': case report of a family2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 4, p. 277-281Article in journal (Refereed)
    Abstract [en]

    We report the observation of an 18-year-old girl, whose clinical presentation was very suggestive of a congenital myopathy with neonatal onset. A congenital myopathy had been already diagnosed in her brother and in addition her half-cousin died diagnosed with a severe nemaline myopathy at age 4 years. A muscle biopsy performed on both siblings revealed histological and ultrastructural features of 'cap myopathy'. This case report suggests that 'cap myopathy' and some cases of nemaline myopathy with neonatal onset might be two phenotypic expressions of the same genetic disorder. These two entities could therefore, perhaps, be regarded as 'Z-line disorders' possibly caused by defective myofibrillogenesis.

  • 6.
    Dahl-Halvarsson, Martin
    et al.
    University of Gothenburg, Gothenburg, Sweden.
    Olive, Montse
    Institut Investigació Biomèdica de Bellvitge – Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
    Pokrzywa, Malgorzata
    University of Gothenburg, Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Palmer, Ruth H.
    University of Gothenburg, Gothenburg, Sweden.
    Uv, Anne Elisabeth
    University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 28, p. E6566-E6575Article in journal (Refereed)
    Abstract [en]

    Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

  • 7.
    Dahl-Halvarsson, Martin
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Olive, Montse
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain.
    Pokrzywa, Malgorzata
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Norum, Michaela
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sweden.
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase2020In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 13, no 12, article id dmm047886Article in journal (Refereed)
    Abstract [en]

    Myosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/ß-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases with myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of R1845W mutation. This study shows that higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase.This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities including extensive loss of thick filaments with selective A-band loss and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Further, the impaired muscle morphology associated with the mutant allele was supressed by expression of Abba/Thin, an E3 ubiquitin ligase. These findings suggest that modification of ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

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  • 8.
    Dahl-Halvarsson, Martin
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Pokrzywa, Malgorzata
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Rauthan, Manish
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Pilon, Marc
    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells2017In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 1, article id e0170613Article in journal (Refereed)
    Abstract [en]

    Myosin storage myopathy is a protein aggregate myopathy associated with the characteristic subsarcolemmal accumulation of myosin heavy chain in muscle fibers. Despite similar histological findings, the clinical severity and age of onset are highly variable, ranging from no weakness to severe impairment of ambulation, and usually childhood-onset to onset later in life. Mutations located in the distal end of the tail of slow/beta-cardiac myosin heavy chain are associated with myosin storage myopathy. Four missense mutations (L1793P, R1845W, E1883K and H1901L), two of which have been reported in several unrelated families, are located within or closed to the assembly competence domain. This location is critical for the proper assembly of sarcomeric myosin rod filaments. To assess the mechanisms leading to protein aggregation in myosin storage myopathy and to evaluate the impact of these mutations on myosin assembly and muscle function, we expressed mutated myosin proteins in cultured human muscle cells and in the nematode Caenorhabditis elegans. While L1793P mutant myosin protein efficiently incorporated into the sarcomeric thick filaments, R1845W and H1901L mutants were prone to formation of myosin aggregates without assembly into striated sarcomeric thick filaments in cultured muscle cells. In C. elegans, mutant alleles of the myosin heavy chain gene unc-54 corresponding to R1845W, E1883K and H1901L, were as effective as the wild-type myosin gene in rescuing the null mutant worms, indicating that they retain functionality. Taken together, our results suggest that the basis for the pathogenic effect of the R1845W and H1901L mutations are primarily structural rather than functional. Further analyses are needed to identify the primary trigger for the histological changes seen in muscle biopsies of patients with L1793P and E1883K mutations.

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  • 9.
    Darin, Niklas
    et al.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden / Department of Pediatrics, Queen Silvia Children's Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Östman-Smith, I.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Gilljam, T.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New skeletal myopathy and cardiomyopathy associated with a missense mutation in MYH72007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 23, p. 2041-2042Article in journal (Refereed)
  • 10.
    Kariminejad, Ariana
    et al.
    Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran.
    Almadani, Navid
    Kariminejad-Najmabadi Pathology & Genetics Centre, Tehran, Iran.
    Khoshaeen, Atefeh
    Mehrgan Genetics Centre, Sari, Iran.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome2016In: BMC Genetics, E-ISSN 1471-2156, Vol. 17, no 1, article id 71Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:In humans, muscle-specific nicotinergic acetylcholine receptor (AChR) is a transmembrane protein with five different subunits, coded by CHRNA1, CHRNB, CHRND and CHRNG/CHRNE. The gamma subunit of AChR encoded by CHRNG is expressed during early foetal development, whereas in the adult, the γ subunit is replaced by a ε subunit. Mutations in the CHRNG encoding the embryonal acetylcholine receptor may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome. The MPS is a condition characterised by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis.

    RESULTS:Our whole exome sequencing studies have identified one novel and two previously reported homozygous mutations in CHRNG in three families affected by non-lethal EVMPS. The mutations consist of deletion of two nucleotides, cause a frameshift predicted to result in premature termination of the foetally expressed gamma subunit of the AChR.

    CONCLUSIONS:Our data suggest that severity of the phenotype varies significantly both within and between families with MPS and that there is no apparent correlation between mutation position and clinical phenotype. Although individuals with CHRNG mutations can survive, there is an increased frequency of abortions and stillbirth in their families. Furthermore, genetic background and environmental modifiers might be of significance for decisiveness of the lethal spectrum, rather than the state of the mutation per se. Detailed clinical examination of our patients further indicates the changing phenotype from infancy to childhood.

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  • 11.
    Kariminejad, Ariana
    et al.
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Dahl-Halvarsson, Martin
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Ravenscroft, Gianina
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Afroozan, Fariba
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Keshavarz, Elham
    Department of Radiology, Mahdieh Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran.
    Goullée, Hayley
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Davis, Mark R.
    Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Nedlands, Western Australia, Australia.
    Faraji Zonooz, Mehrshid
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Najmabadi, Hossein
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Laing, Nigel G.
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor2017In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 140, no 11, p. 2851-2859Article in journal (Refereed)
    Abstract [en]

    Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A.

    We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation.

    Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations. 

  • 12.
    Kariminejad, Ariana
    et al.
    Najmabadi Pathology & Genetics Center, Tehran, Iran.
    Ghaderi-Sohi, Siavash
    Najmabadi Pathology & Genetics Center, Tehran, Iran.
    Hossein-Nejad Nedai, Hamid
    Department of Pathology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Varasteh, Vahid
    Division of Thoracic Surgery, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum2016In: BMC Musculoskeletal Disorders, E-ISSN 1471-2474, Vol. 17, no 1, p. 1-5, article id 109Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Lethal multiple pterygium syndrome (LMPS, OMIM 253290), is a fatal disorder associated with anomalies of the skin, muscles and skeleton. It is characterised by prenatal growth failure with pterygium present in multiple areas and akinesia, leading to muscle weakness and severe arthrogryposis. Foetal hydrops with cystic hygroma develops in affected foetuses with LMPS. This study aimed to uncover the aetiology of LMPS in a family with two affected foetuses.

    METHODS AND RESULTS: Whole exome sequencing studies have identified novel compound heterozygous mutations in RYR1 in two affected foetuses with pterygium, severe arthrogryposis and foetal hydrops with cystic hygroma, characteristic features compatible with LMPS. The result was confirmed by Sanger sequencing and restriction fragment length polymorphism analysis.

    CONCLUSIONS: RYR1 encodes the skeletal muscle isoform ryanodine receptor 1, an intracellular calcium channel with a central role in muscle contraction. Mutations in RYR1 have been associated with congenital myopathies, which form a continuous spectrum of pathological features including a severe variant with onset in utero with fetal akinesia and arthrogryposis. Here, the results indicate that LMPS can be considered as the extreme end of the RYR1-related neonatal myopathy spectrum. This further supports the concept that LMPS is a severe disorder associated with defects in the process known as excitation-contraction coupling.

  • 13.
    Kariminejad, Ariana
    et al.
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Szenker-Ravi, Emmanuelle
    Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore.
    Lekszas, Caroline
    Institute of Human Genetics, Julius-Maximilians-Universität, Würzburg, Germany.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Moslemi, Ali-Reza
    Institute of Biomedicine, Sahlgrenska University Hospital, Gothenburg University, Sweden.
    Naert, Thomas
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Tran, Hong Thi
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Ahangari, Fatemeh
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehra, Iran.
    Rajaei, Minoo
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Nasseri, Mojila
    Pardis Clinical and Genetics Laboratory, Mashhad, Iran.
    Haaf, Thomas
    Institute of Human Genetics, Julius-Maximilians-Universität, Würzburg, Germany.
    Azad, Afrooz
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Superti-Furga, Andrea
    Division of Genetic Medicine, Lausanne University Hospital (CHUV), University of Lausanne, Switzerland.
    Maroofian, Reza
    Molecular and Clinical Sciences Institute, St. George’s University of London, UK.
    Ghaderi-Sohi, Siavash
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran.
    Najmabadi, Hossein
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran Iran / Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
    Abbaszadegan, Mohammad Reza
    Pardis Clinical and Genetics Laboratory, Mashhad, Iran / Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
    Vleminckx, Kris
    Department of Biomedical Molecular Biology, Ghent University, Belgium.
    Nikuei, Pooneh
    Fertility and Infertility Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
    Reversade, Bruno
    Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore / Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, Singapore, Republic of Singapore / Department of Medical Genetics, Koç University, School of Medicine, Topkapı, Istanbul, Turkey.
    Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia2019In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 105, no 6, p. 1294-1301Article in journal (Refereed)
    Abstract [en]

    The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113 and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113 stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.

  • 14.
    Kimber, Eva
    et al.
    Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden / .
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Kroksmark, A.-K.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Sweden.
    Tulinius, M.
    Queen Silvia Children's Hospital, Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
    A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis.2006In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 67, no 4, p. 597-601Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2.

    METHODS: The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2.

    RESULTS: The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members.

    CONCLUSION: Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.

  • 15.
    Kimber, Eva
    et al.
    Department of Women’s and Children’s Health, Uppsala University Children’s Hospital, Uppsala, Sweden / Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kroksmark, Anna-Karin
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tulinius, Már
    Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
    Distal arthrogryposis: clinical and genetic findings2012In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 101, no 8, p. 877-887Article in journal (Refereed)
    Abstract [en]

    AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation.

    METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed.

    RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection.

    CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.

  • 16.
    Lee, Richard G.
    et al.
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia.
    Sedghi, Maryam
    Univ Isfahan, Dept Genet, Esfahan, Iran.
    Salari, Mehri
    Shahid Beheshti Univ Med Sci, Shohada Tajrish Neurosurg Ctr Excellence, Funct Neurosurg Res Ctr, Tehran, Iran.
    Shearwood, Anne-Marie J.
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia.
    Stentenbach, Maike
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia.
    Kariminejad, Ariana
    Kariminejad Najmabadi Pathol & Genet Ctr, Tehran, Iran.
    Goullee, Hayley
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia.
    Rackham, Oliver
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia / Univ Western Australia, Sch Mol Sci, Crawley, Australia.
    Laing, Nigel G.
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia / QEII Med Ctr, PathWest, Dept Diagnost Genom, Nedlands, WA, Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education.
    Filipovska, Aleksandra
    Univ Western Australia, Ctr Med Res, Nedlands, WA, Australia / Harry Perkins Inst Med Res, Nedlands, WA, Australia / Univ Western Australia, Sch Mol Sci, Crawley, Australia.
    Early-onset Parkinson disease caused by a mutation in CHCHD2 and mitochondrial dysfunction2018In: Neurology Genetics, ISSN 2376-7839, Vol. 4, no 5, article id e276Article in journal (Refereed)
    Abstract [en]

    Objective Our goal was to identify the gene(s) associated with an early-onset form of Parkinson disease (PD) and the molecular defects associated with this mutation. Methods We combined whole-exome sequencing and functional genomics to identify the genes associated with early-onset PD. We used fluorescence microscopy, cell, and mitochondrial biology measurements to identify the molecular defects resulting from the identified mutation. Results Here, we report an association of a homozygous variant in CHCHD2, encoding coiled-coil-helix-coiled-coil-helix domain containing protein 2, a mitochondrial protein of unknown function, with an early-onset form of PD in a 26-year-old Caucasian woman. The CHCHD2 mutation in PD patient fibroblasts causes fragmentation of the mitochondrial reticular morphology and results in reduced oxidative phosphorylation at complex I and complex IV. Although patient cells could maintain a proton motive force, reactive oxygen species production was increased, which correlated with an increased metabolic rate. Conclusions Our findings implicate CHCHD2 in the pathogenesis of recessive early-onset PD, expanding the repertoire of mitochondrial proteins that play a direct role in this disease.

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  • 17.
    Li, M.
    et al.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Jinan, China.
    Lionikas, A.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Yu, F.
    Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, L.
    Department of Clinical Neurophysiology, Uppsala University, Uppsala, Sweden / Center for Developmental and Health Genetics, The Pennsylvania State University, University Park, PA, USA.
    Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)2006In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 11, p. 782-791Article in journal (Refereed)
    Abstract [en]

    The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

  • 18.
    Lossos, Alexander
    et al.
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Fellig, Yakov
    Department of Pathology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Meiner, Vardiella
    Department of Genetics, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Argov, Zohar
    Department of Neurology, Hebrew University-Hadassah Medical Centre, Jerusalem, Israel.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    MYH2 mutation in recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p122013In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 136, no 7, article id e238Article in journal (Refereed)
  • 19.
    Maroofian, Reza
    et al.
    Department of Neuromuscular Diseases, University College London, Institute of Neurology, United Kingdom.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Severino, Mariasavina
    Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
    Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders2023In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 12, p. 5031-5043Article in journal (Refereed)
    Abstract [en]

    MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. 

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  • 20.
    Moslemi, Ali-Reza
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Institute of Physiology and Neurological Sciences, University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Johanna
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Andersson, Bert
    Department of Cardiology, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Glycogenin-1 deficiency and inactivated priming of glycogen synthesis2010In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 362, no 13, p. 1203-1210Article in journal (Refereed)
    Abstract [en]

    Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.

  • 21.
    Nilipour, Yalda
    et al.
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Nafissi, Shahriar
    Tehran University of Medical Sciences, Iran.
    Tjust, Anton E.
    Umeå University, Sweden.
    Ravenscroft, Gianina
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Hossein-Nejad Nedai, Hamid
    Shahid Beheshti University of Medical Sciences, Iran.
    Taylor, Rhonda L.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Varasteh, Vahid
    Shahid Beheshti University of Medical Sciences, Iran.
    Pedrosa Domellöf, Fatima
    Umeå University, Sweden.
    Zangi, Mahdi
    National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Iran.
    Tonekaboni, Seyed Hassan
    Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Iran.
    Olivé, M.
    IDIBELL-Hospital de Bellvitge, Barcelona, Spain.
    Kiiski, Kirsi
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Sagath, L.
    Folkhälsan Institute of Genetics, Medicum, University of Helsinki, Finland.
    Davis, Mark R.
    Pathwest, QEII Medical Centre, Nedlands, Western Australia.
    Laing, Nigel G.
    The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Western Australia, Australia.
    Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies2018In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, no 6, p. 841-847Article in journal (Refereed)
    Abstract [en]

    Background: Nemaline myopathy has been associated with mutations in twelve genes to date. However, for some patients diagnosed with nemaline myopathy, definitive mutations are not identified in the known genes, suggesting there are other genes involved. This study describes compound heterozygosity for rare variants in RYR3 in one such patient.

    Results: Clinical examination of the patient at 22 years of age revealed a long-narrow face, high arched palate and bilateral facial weakness. She had proximal weakness in all four limbs, mild scapular winging but no scoliosis. Muscle biopsy revealed wide variation in fibre size with type 1 fibre predominance and atrophy. Abundant nemaline bodies were located in perinuclear areas, subsarcolemmal and within the cytoplasm. No likely pathogenic mutations in known nemaline myopathy genes were identified. Copy number variation in known nemaline myopathy genes was excluded by nemaline myopathy targeted array-CGH. Next generation sequencing revealed compound heterozygous missense variants in the ryanodine receptor type 3 gene (RYR3).  RYR3 transcripts are expressed in human fetal and adult skeletal muscle as well as in human brain or cauda equina samples. Immunofluorescence of human skeletal muscle revealed a "single-row" appearance of RYR3, interspaced between the "double-rows" of RYR1 at each A-I junction.

    Conclusion: The results suggest that variants in RYR3 may cause a recessive muscle disease with pathological features including nemaline bodies. We characterize the expression pattern of RYR3 in human skeletal muscle and brain and the subcellular localization of RYR1 and RYR3 in human skeletal muscle.

  • 22.
    Nilsson, J.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Beta-tropomyosin mutations alter tropomyosin isoform composition2008In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 15, no 6, p. 573-578Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Tropomyosin (TM) is an actin-binding protein, which is localized head to tail along the length of the actin filament. There are three major TM isoforms in human striated muscle. Mutations in beta-tropomyosin (TPM2) have recently been identified as an important cause of neuromuscular disorders.

    MATERIALS AND METHODS: The expression of TM isoforms in patients carrying mutations in TPM2 was detected using a combination of SDS-PAGE, Western blotting, and a new method to measure the relative abundance of the various TM transcripts.

    RESULTS: The level of gamma-TM is reduced in patients with mutations in TPM2. Beta-tropomyosin was expressed at high levels in muscle specimens of the patients.

    DISCUSSION: Our study indicates that beta-TM gene mutations can alter the expression of other sarcomeric TM isoforms and that the perturbation of TM isoform levels may affect the dimer preference within the thin filaments, which may contribute to muscle weakness as a result of both functional and structural changes in muscle.

  • 23.
    Ochala, Julien
    et al.
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden.
    Li, Mingxin
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Department of Neurology, Qilu Hospital, Shandong University, Shandong, China.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Department of Neuropaediatrics, Uppsala University Children's Hospital, Sweden.
    Tulinius, Mar
    The Queen Silvia Children's Hospital, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Larsson, Lars
    Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden / Center for Development and Health Genetics, Pennsylvania State University, University Park, PA, United States.
    Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres2007In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, p. 1283-1292Article in journal (Refereed)
    Abstract [en]

    A novel R133W beta-tropomyosin (beta-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the beta-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the beta-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P<0.05) and ktr (P<0.01), and a faster V0 (P<0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W beta-Tm mutation. It is suggested that the R133W beta-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

  • 24.
    Ohlsson, M.
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Quijano-Roy, S.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Darin, N.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Brochier, G.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Lacène, E.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Avila-Smirnow, D.
    AP-HP, Service de Pédiatrie, Centre National de Référence des Maladies Neuromusculaires GNMH, Garches, France.
    Fardeau, M.
    Institut de Myologie, Groupe Hospitalier Pitie-Salpêtrière, Paris, France.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations2008In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 71, no 23, p. 1896-1901Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2.

    METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis.

    RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys).

    CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

  • 25.
    Ohlsson, M.
    et al.
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, N.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, M.
    Department of Pediatrics, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Göteborg Neuromuscular Center, Sahlgrenska University Hospital, Göteborg, Sweden.
    Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1)2004In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 14, no 8-9, p. 471-475Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.

  • 26.
    Ohlsson, Monica
    et al.
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hedberg, Carola
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Brådvik, Björn
    Department of Clinical Sciences, Division of Neurology, Lund University, Lund, Sweden.
    Lindberg, Christopher
    Department of Neurology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Danielsson, Olof
    Division of Neurology, Department of Clinical and Experimental Medicine, University Hospital Linköping, Linköping, Sweden.
    Melberg, Atle
    Department of Neuroscience, Neurology, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
    Udd, Bjarne
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.
    Martinsson, Tommy
    Department of Clinical Genetics, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin2012In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 135, no 6, p. 1682-1694Article in journal (Refereed)
    Abstract [en]

    Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

  • 27.
    Oldfors, Anders
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Paediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Lindberg, Christopher
    Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Myopathies associated with myosin heavy chain mutations2004In: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases, ISSN 1128-2460, Vol. 23, no 2, p. 90-96Article in journal (Refereed)
    Abstract [en]

    Myosin, a molecular motor, converts chemical energy into mechanical force. The motor domain of myosin heavy chain (MyHC) includes an ATP binding region with ATPase activity and an actin-binding region. Motor function is achieved by conformational changes, at hydrolysis, of ATP causing a shift in the angle between the actin binding head and the rod region of the molecule. The elongated alpha-helical coiled-coil rod region of MyHC molecules constitutes the major part of the thick filaments of the sarcomere. Three major MyHC isoforms are expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres; IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the core of the head of MyHC IIa is associated with a familial congenital myopathy, which, in most instances, has shown mild phenotypic expression in children but progressive course in some adults. There is a relationship between the level of expression of mutated MyHC IIa and muscle pathology. Some adults with a progressive course show muscle fibres with rimmed vacuoles and filaments of the type seen in inclusion body myositis/myopathy (IBM). Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type I, MYH7) is associated with familial congenital myopathy, with large deposits of MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage myopathy". These patients showed slowly progressive muscle weakness but no overt cardiomyopathy. These two muscle diseases, which are caused by mutations in MyHC, form the basis of a novel entity: "Myosin myopathies".

  • 28.
    Oldfors, Anders
    et al.
    Göteborg, Sweden.
    Tajsharghi, Homa
    Göteborg, Sweden.
    Thornell, L. E.
    Mutation of the slow myosin heavy chain rod domain underlies hyaline body myopathy2005In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 64, no 3, p. 580-581Article in journal (Refereed)
  • 29.
    Olivé, Montse
    et al.
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Abdul-Hussein, Saba
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    González-Costello, José
    Department of Cardiology, Barcelona, Spain.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Fürst, Dieter O.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    González, Laura
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology.
    Moreno, Dolores
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain.
    Torrejón-Escribano, Benjamín
    Scientific and Technical Services Facility, Biology Unit, CCiTUB, IDIBELL-University of Barcelona, Barcelona, Spain.
    Alió, Josefina
    Department of Cardiology, Barcelona, Spain.
    Pou, Adolf
    Department of Neurology, Hospital del Mar, Barcelona, Spain.
    Ferrer, Isidro
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden / Department of Clinical and Medical Genetics, University of Gothenburg, Gothenburg, Sweden.
    New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 13, p. 3638-3650, article id 108Article in journal (Refereed)
    Abstract [en]

    Protein aggregate myopathies (PAMs) define muscle disorders characterized by protein accumulation in muscle fibres. We describe a new PAM in a patient with proximal muscle weakness and hypertrophic cardiomyopathy, whose muscle fibres contained inclusions containing myosin and myosin-associated proteins, and aberrant distribution of microtubules. These lesions appear as intact A- and M-bands lacking thin filaments and Z-discs. These features differ from inclusions in myosin storage myopathy (MSM), but are highly similar to those in mice deficient for the muscle-specific RING finger proteins MuRF1 and MuRF3. Sanger sequencing excluded mutations in the MSM-associated gene MYH7 but identified mutations in TRIM63 and TRIM54, encoding MuRF1 and MuRF3, respectively. No mutations in other potentially disease-causing genes were identified by Sanger and whole exome sequencing. Analysis of seven family members revealed that both mutations segregated in the family but only the homozygous TRIM63 null mutation in combination with the heterozygous TRIM54 mutation found in the proband caused the disease phenotype. Both MuRFs are microtubule-associated proteins localizing to sarcomeric M-bands and Z-discs. They are E3 ubiquitin ligases that play a role in degradation of sarcomeric proteins, stabilization of microtubules and myogenesis. Lack of ubiquitin and the 20S proteasome subunit in the inclusions found in the patient suggested impaired turnover of thick filament proteins. Disruption of microtubules in cultured myotubes was rescued by transient expression of wild-type MuRF1. The unique features of this novel myopathy point to defects in homeostasis of A-band proteins in combination with instability of microtubules as cause of the disease.

  • 30.
    Olivé, Montse
    et al.
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Abdul-Hussein, Saba
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Oldfors, Anders
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    González-Costello, José
    Department of Cardiology, Barcelona, Spain.
    van der Ven, Peter F. M.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    Fürst, Dieter O.
    Department of Molecular Cell Biology, Institute for Cell Biology, University of Bonn, Bonn, Germany.
    González, Laura
    Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology.
    Moreno, Dolores
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain.
    Torrejón-Escribano, Benjamín
    Scientific and Technical Services Facility, Biology Unit, CCiTUB, IDIBELL-University of Barcelona, Barcelona, Spain.
    Alió, Josefina
    Department of Cardiology, Barcelona, Spain.
    Pou, Adolf
    Department of Neurology, Hospital del Mar, Barcelona, Spain.
    Ferrer, Isidro
    Institute of Neuropathology, Department of Pathology, Barcelona, Spain / CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto Carlos III, Barcelona, Spain.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations: [Human Molecular Genetics, 24, 13, (2015) 3638-3650] DOI: 10.1093/hmg/ddv108 [Erratum]2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 21, p. 6264-6264Article in journal (Refereed)
  • 31.
    Osborn, Daniel Peter Sayer
    et al.
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Emrahi, Leila
    Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University Tehran, Iran.
    Clayton, Joshua
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Tabrizi, Mehrnoush Toufan
    Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
    Wan, Alex Yui Bong
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Maroofian, Reza
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Yazdchi, Mohammad
    Centre for Neuroscience Research center, Tabriz University of medical science, Tabriz, Iran.
    Garcia, Michael Leon Enrique
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Galehdari, Hamid
    Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Iran.
    Hesse, Camila
    Institute of Biomedicine, Sahlgrenska academy, University of Gothenburg, Sweden.
    Shariati, Gholamreza
    Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
    Mazaheri, Neda
    Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Iran.
    Sedaghat, Alireza
    Health Research Institute, Diabetes Research Center, Ahvaz Jundishapur University of medical Sciences, Ahvaz, Iran.
    Goullée, Hayley
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Laing, Nigel
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Jamshidi, Yalda
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St George’s University of London, United Kingdom.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
    Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL32021In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 23, no 4, p. 787-792Article in journal (Refereed)
    Abstract [en]

    Purpose: Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. Methods: Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. Results: Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood–onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C&gt;A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G&gt;T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G&gt;A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G&gt;T or the missense c.170C&gt;A variants. Minigene assay of the c.482-1G&gt;A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. Conclusions: Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function. 

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  • 32.
    Pagnamenta, Alistair T.
    et al.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Diaz-Gonzalez, Francisca
    NGEMM, IdiPAZ and Skeletal Dysplasia Multidisciplinary Unit (UMDE, ERN-BOND), Hospital Universitario La Paz, Madrid, Spain.
    Banos-Pinero, Benito
    Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Ferla, Matteo P.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Toosi, Mehran B.
    Department of Pediatric Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Iran.
    Calder, Alistair D.
    Radiology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
    Karimiani, Ehsan G.
    Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George’s, University of London, UK ; Next Generation Genetic Polyclinic, Razavi International Hospital, Mashhad, Iran.
    Doosti, Mohammad
    Next Generation Genetic Polyclinic, Razavi International Hospital, Mashhad, Iran.
    Wainwright, Andrew
    Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Wordsworth, Paul
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK ; Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Bailey, Kathryn
    Department of Paediatrics, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Ejeskär, Katarina
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Lester, Tracy
    Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Maroofian, Reza
    Department of Neuromuscular Disorders, Queen Square Institute of Neurology, UCL, London, UK.
    Heath, Karen E.
    INGEMM, IdiPAZ and Skeletal Dysplasia Multidisciplinary Unit (UMDE, ERN-BOND), Hospital Universitario La Paz, Madrid, Spain ; CIBERER, ISCIII, Madrid, Spain .
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Shears, Deborah
    Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
    Taylor, Jenny C.
    NIHR Biomedical Research Centre, Oxford, UK ; Wellcome Centre for Human Genetics, Oxford University, UK.
    Variable skeletal phenotypes associated with biallelic variants in PRKG22022In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 59, no 10, p. 947-950Article in journal (Refereed)
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  • 33.
    Pagnamenta, Alistair T.
    et al.
    NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, UK.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Houlden, Henry
    Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
    An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy2021In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 144, no 2, p. 584-600Article in journal (Refereed)
    Abstract [en]

    The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

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  • 34.
    Pokrzywa, Malgorzata
    et al.
    Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
    Norum, Michaela
    Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
    Lengqvist, Johan
    Proteomic Core Facility, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Ghobadpour, Mehrnaz
    Department of Clinical and Medical Genetics, University of Gothenburg, Sweden.
    Abdul-Hussein, Saba
    Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Moslemi, Ali-Reza
    Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Tajsharghi, Homa
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142094Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    An essential role for embryonic MyHC in foetal development has been found from its association with distal arthrogryposis syndromes, a heterogeneous group of disorders characterised by congenital contractions. The latter probably result from severe myopathy during foetal development. Lack of embryonic muscle biopsy material and suitable animal models has hindered study of the pathomechanisms linking mutations in MYH3 to prenatal myopathy.

    METHODS AND RESULTS:

    We determined the pathomechanisms of developmental myopathy caused by recurrent p.Thr178Ile MYH3 heterozygosity, using patient-derived skeletal muscle cells in culture as an experimental disease model to emulate early embryonic development. These cultured cells were processed for discrimination and quantitative analysis of mutant and wild-type MYH3 alleles and MyHC transcripts, real-time RT-qPCR, sequence analysis, immunofluorescence microscopy, immunoblot, and proteomic assessments. Involvement of the ubiquitin proteasome system was investigated in patients with p.Thr178Ile mutations in MYH3 and MYH2. We found equal overall expression of mutant and wild-type MyHC mRNAs and proteins. Compared to the controls, however, expression of embryonic MyHC transcripts and proteins was reduced whereas expression of myosin-specific E3 ubiquitin ligase (MuRF1) was increased. We also found delayed myofibrillogenesis and atrophic myotubes but structured sarcomeres.

    CONCLUSION:

    In conclusion, this study suggests that developmental p.Thr178Ile MYH3 myopathy is associated with a combined pathomechanism of insufficient dosage of functional embryonic MyHC and production of mutant protein.

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  • 35.
    Rosenhahn, Erik
    et al.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    O'Brien, Thomas J.
    MRC London Institute of Medical Sciences, United Kingdom.
    Zaki, Maha S.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Sorge, Ina
    Department of Pediatric Radiology, University Hospital Leipzig, Germany.
    Wieczorek, Dagmar
    Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany.
    Rostasy, Kevin
    Department of Pediatric Neurology, Children's and Adolescents’ Hospital Datteln, Witten/Herdecke University, Germany.
    Vitobello, Antonio
    UF6254 Innovation en Diagnostic Genomique des Maladies Rares, CHU Dijon Bourgogne, FHU translad, Génétique des Anomalies du Développement, INSERM UMR 1231, Université de Bourgogne-Franche Comté, Dijon, France.
    Nambot, Sophie
    Centre de Génétique et Centre de référence des Maladies rare, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, France.
    Alkuraya, Fowsan S.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia ; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
    Hashem, Mais O.
    Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
    Alhashem, Amal
    Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia ; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Tabarki, Brahim
    Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
    Alamri, Abdullah S.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Al Safar, Ayat H.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Bubshait, Dalal K.
    Department of Pediatrics, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Alahmady, Nada F.
    Biology Department, Imam Abdulrahman bin Faisal University, Dammam, Saudi Arabia.
    Gleeson, Joseph G.
    Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA ; Rady Children’s Institute for Genomic Medicine, San Diego, La Jolla, CA, USA.
    Abdel-Hamid, Mohamed S.
    Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Lesko, Nicole
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Ygberg, Sofia
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Neuropediatric Unit, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden.
    Correia, Sandrina P.
    Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden ; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Wredenberg, Anna
    Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Alavi, Shahryar
    Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Iran ; Palindrome, Isfahan, Iran.
    Seyedhassani, Seyed M.
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Ebrahimi Nasab, Mahya
    Dr. Seyedhassani Medical Genetic Center, Yazd, Iran.
    Hussien, Haytham
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Omar, Tarek E. I.
    Alexandria University Children’s Hospital, Faculty of Medicine, Alexandria University, Egypt.
    Harzallah, Ines
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Touraine, Renaud
    Clinical, Chromosomal and Molecular Genetics Department, University Hospital Center, Saint-Étienne, France.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Morsy, Heba
    UCL Queen Square Institute of Neurology, University College London, UK.
    Houlden, Henry
    UCL Queen Square Institute of Neurology, University College London, UK.
    Shahrooei, Mohammad
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran ; Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Belgium.
    Ghavideldarestani, Maryam
    Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
    Abdel-Salam, Ghada M. H.
    Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
    Torella, Annalaura
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy ; Telethon Institute of Genetics and Medicine, Naples, Italy.
    Zanobio, Mariateresa
    Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.
    Terrone, Gaetano
    Child Neurology Unit, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy.
    Brunetti-Pierri, Nicola
    Telethon Institute of Genetics and Medicine, Naples, Italy ; Department of Translational Medicine, Section of Pediatrics, University of Naples Federico II, Italy.
    Omrani, Abdolmajid
    Division of Clinical Studies, The Persian Gulf Nuclear Medicine Research Center, Bushehr University of Medical Sciences, Iran.
    Hentschel, Julia
    Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
    Lemke, Johannes R.
    Institute of Human Genetics, University of Leipzig Medical Center, Germany ; Center for Rare Diseases, University of Leipzig Medical Center, Germany.
    Sticht, Heinrich
    Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
    Abou Jamra, Rami
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Brown, Andre E. X.
    MRC London Institute of Medical Sciences, UK ; Faculty of Medicine, Institute of Clinical Sciences, Imperial College London, UK ; .
    Maroofian, Reza
    UCL Queen Square Institute of Neurology, University College London, UK.
    Platzer, Konrad
    Institute of Human Genetics, University of Leipzig Medical Center, Germany.
    Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications2022In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, no 8, p. 1421-1435Article in journal (Refereed)
    Abstract [en]

    PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications. 

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  • 36.
    Saffari, Afshin
    et al.
    Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA ; Division of Child Neurology and Inherited Metabolic Diseases, Heidelberg University Hospital, Germany.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Maroofian, Reza
    Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, UK.
    The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders2023In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 8, p. 3273-3288, article id awad039Article in journal (Refereed)
    Abstract [en]

    In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival.

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  • 37.
    Sedghi, Maryam
    et al.
    Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Iran.
    Moslemi, Ali-Reza
    Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Sweden.
    Cabrera-Serrano, Macarena
    Department of Neurology, Hospital Universitario Virgen del Rocio, Sevilla, Spain / Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Spain.
    Ansari, Behnaz
    Department of neurology, Isfahan University of Medical Sciences, Iran.
    Ghasemi, Majid
    Department of neurology, Isfahan University of Medical Sciences, Iran.
    Baktashian, Mojtaba
    Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Iran.
    Fattahpour, Ali
    Radiology Resident, Department of Radiology, Mashhad University of Medical Sciences, Iran.
    Tajsharghi, Homa
    University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR).
    Recessive Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP2019In: Brain Communications, E-ISSN 2632-1297, Vol. 1, no 1, p. 1-9, article id fcz011Article in journal (Refereed)
    Abstract [en]

    Variants in MCM3AP, encoding the germinal-centre associated nuclear protein, have been associated with progressive polyneuropathy with or without intellectual disability and ptosis in some cases, and with a complex phenotype with immunodeficiency, skin changes and myelodysplasia. MCM3AP encoded protein functions as an acetyltransferase that acetylates the replication protein, MCM3, and plays a key role in the regulation of DNA replication. In this study, we report a novel variant in MCM3AP (p.Ile954Thr), in a family including three affected individuals with characteristic features of Charcot-Marie-Tooth neuropathy and multiple sclerosis, an inflammatory condition of the central nervous system without known genetic cause. The affected individuals were homozygous for a missense MCM3AP variant, located at the Sac3 domain, which was predicted to affect conserved amino acid likely important for the function of the germinal-centre associated nuclear protein. Our data support further expansion of the clinical spectrum linked to MCM3AP variant and highlight that MCM3AP should be considered in patients with accompaniment of recessive motor axonal Charcot-Marie-Tooth neuropathy and multiple sclerosis.

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  • 38.
    Sedghi, Maryam
    et al.
    Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Iran.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Olive, Montse
    Institute of Neuropathology, Department of Pathology, Institut Investigacio Biomedica de Bellvitge (IDIBELL)-Hospital de Bellvitge, Hospitalet de Llobregat, Spain / Neuromuscular Unit, Department of Neurology, Institut Investigacio Biomedica de Bellvitge-(IDIBELL)-Hospital de Bellvitge, Hospitalet de Llobregat, Spain.
    Etemadifar, Masoud
    Department of Functional Neursurgery, Faculty of Medicine, Isfahan University of Medical Sciences, Iran.
    Ansari, Behnaz
    Department of Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Iran.
    Nasiri, Jafar
    Department of Pediatric Neurology, Faculty of Medicine, Isfahan University of Medical Sciences, Iran.
    Emrahi, Leila
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Mianesaz, Hamid-Reza
    Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Iran.
    Laing, Nigel G.
    Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Centre for Medical Research, The University of Western Australia and the Harry Perkins Institute for Medical Research, Nedlands, Australia.
    Motor neuron diseases caused by a novel VRK1 variant - A genotype/phenotype study2019In: Annals of Clinical and Translational Neurology, E-ISSN 2328-9503, Vol. 6, no 11, p. 2197-2204Article in journal (Refereed)
    Abstract [en]

    Background Motor neuron disorders involving upper and lower neurons are a genetically and clinically heterogenous group of rare neuromuscular disorders with overlap among spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS). Classical SMA caused by recessive mutations in SMN1 is one of the most common genetic causes of mortality in infants. It is characterized by degeneration of anterior horn cells in the spinal cord, leading to progressive muscle weakness and atrophy. Non-SMN1-related spinal muscular atrophies are caused by variants in a number of genes, including VRK1, encoding the vaccinia-related kinase 1 (VRK1). VRK1 variants have been segregated with motor neuron diseases including SMA phenotypes or hereditary complex motor and sensory axonal neuropathy (HMSN), with or without pontocerebellar hypoplasia or microcephaly. Results Here, we report an association of a novel homozygous splice variant in VRK1 (c.1159 + 1G>A) with childhood-onset SMA or juvenile lower motor disease with brisk tendon reflexes without pontocerebellar hypoplasia and normal intellectual ability in a family with five affected individuals. We show that the VRK1 splice variant in patients causes decreased splicing efficiency and a mRNA frameshift that escapes the nonsense-mediated decay machinery and results in a premature termination codon. Conclusions Our findings unveil the impact of the variant on the VRK1 transcript and further support the implication of VRK1 in the pathogenesis of lower motor neuron diseases.

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  • 39.
    Sedghi, Maryam
    et al.
    Medical Genetics Laboratory, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.
    Salari, Mehri
    Department of Neurology, Shahid Beheshti University of Medical Science, Tehran, Iran.
    Moslemi, Ali-Reza
    Department of Pathology, University of Gothenburg, Sahlgrenska University Hospital, Sweden.
    Kariminejad, Ariana
    Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
    Davis, Mark
    Department of Diagnostic Genomics, Pathwest, QEII Medical Centre, Australia.
    Goullée, Hayley
    Centre for Medical Research, University of Western Australia / Harry Perkins Institute for Medical Research, Nedlands, Australia.
    Olsson, Björn
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre.
    Laing, Nigel
    Centre for Medical Research, University of Western Australia / Harry Perkins Institute for Medical Research, Nedlands, Australia.
    Tajsharghi, Homa
    University of Skövde, School of Health and Education. University of Skövde, Health and Education. Centre for Medical Research, University of Western Australia / Harry Perkins Institute for Medical Research, Nedlands, Australia.
    Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant2018In: Neurology: Genetics, ISSN 2376-7839, Vol. 4, no 6, article id e295Article in journal (Refereed)
    Abstract [en]

    Objective We report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous MRE11 synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency. Methods Clinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed. Results The patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in MRE11 (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of MRE11 transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein. Conclusions Despite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life. 

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  • 40.
    Sunnerhagen, Katharina S.
    et al.
    Department of Clinical Neuroscience-Rehabilitation Medicine, University of Göteborg, Sahlgrenska Hospital, Göteborg, Sweden.
    Darin, N.
    Department of Pediatrics, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    The effects of endurance training in persons with a hereditary myosin myopathy2004In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 110, no 2, p. 80-86Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate muscle performance and its consequences in eight individuals with a hereditary myopathy and the effects of an 8-week endurance training program.

    MATERIAL AND METHODS: Handgrip, muscle strength and endurance and oxygen consumption by breath-by-breath analysis during a stepless bicycle ergonometer test were evaluated. Walking, balance test and activities of daily living (ADL) were assessed, and a questionnaire for activity level and perceived symptoms was used. The design was a before-after trial in comparison with data from a control population, bicycling at 70% of maximal workload, 30 min/day, 5 days/week for 8 weeks.

    RESULTS: The subjects were weaker than age-matched controls. After training, the peak watt increased by almost 20% (P < 0.05). Muscle strength (flexion/extension) and isometric endurance (40% of maximum at 60 degrees ) did not change significantly. The average self-selected walking speed increased significantly (P < 0.05) from 1.25 to 1.45 m/s. Compliance was excellent and no serious adverse events occurred.

    CONCLUSION: Endurance training seems to function for this myopathy.

  • 41.
    Tajsharghi, Homa
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Thick and thin filament gene mutations in striated muscle diseases2008In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 9, no 7, p. 1259-1275Article, review/survey (Refereed)
    Abstract [en]

    The sarcomere is the fundamental unit of cardiac and skeletal muscle contraction. During the last ten years, there has been growing awareness of the etiology of skeletal and cardiac muscle diseases originating in the sarcomere, an important evolving field. Many sarcomeric diseases affect newborn children, i. e. are congenital myopathies. The discovery and characterization of several myopathies caused by mutations in myosin heavy chain genes, coding for the major component of skeletal muscle thick filaments, has led to the introduction of a new entity in the field of neuromuscular disorders: myosin myopathies. Recently, mutations in genes coding for skeletal muscle thin filaments, associated with various clinical features, have been identified. These mutations evoke distinct structural changes within the sarcomeric thin filament. Current knowledge regarding contractile protein dysfunction as it relates to disease pathogenesis has failed to decipher the mechanistic links between mutations identified in sarcomeric proteins and skeletal myopathies, which will no doubt require an integrated physiological approach. The discovery of additional genes associated with myopathies and the elucidation of the molecular mechanisms of pathogenesis will lead to improved and more accurate diagnosis, including prenatally, and to enhanced potential for prognosis, genetic counseling and developing possible treatments for these diseases. The goal of this review is to present recent progress in the identification of gene mutations from each of the major structural components of the sarcomere, the thick and thin filaments, related to skeletal muscle disease. The genetics and clinical manifestations of these disorders will be discussed.

  • 42.
    Tajsharghi, Homa
    et al.
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rekabdar, Elham
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kyllerman, Mårten
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Wahlström, Jan
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Martinsson, Tommy
    Department of Clinical Genetics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Departments of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Mutations and sequence variation in the human myosin heavy chain IIa gene (MYH2)2005In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 13, no 5, p. 617-622Article in journal (Refereed)
    Abstract [en]

    We recently described a new autosomal dominant myopathy associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MYH2). In this study, we performed mutation analysis of MYH2 in eight Swedish patients with familial myopathy of unknown cause. In two of the eight index cases, we identified novel heterozygous missense mutations in MYH2, one in each case: V970I and L1061V. The mutations were located in subfragment 2 of the MyHC and they changed highly conserved residues. Most family members carrying the mutations had signs and symptoms consisting mainly of mild muscle weakness and myalgia. In addition, we analyzed the extent and distribution of nucleotide variation in MYH2 in 50 blood donors, who served as controls, by the complete sequencing of all 38 exons comprising the coding region. We identified only six polymorphic sites, five of which were synonymous polymorphisms. One variant, which occurred at an allele frequency of 0.01, was identical to the L1061V that was also found in one of the families with myopathy. The results of the analysis of normal variation indicate that there is strong selective pressure against mutations in MYH2. On the basis of these results, we suggest that MyHC genes should be regarded as candidate genes in cases of hereditary myopathies of unknown etiology.

  • 43.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Darin, Niklas
    The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, Mar
    The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Early onset myopathy with a novel mutation in the Selenoprotein N gene (SEPN1)2005In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 15, no 4, p. 299-302Article in journal (Refereed)
    Abstract [en]

    Mutations in SEPN1 have been associated with three autosomal recessive congenital myopathies, including rigid spine muscular dystrophy, multiminicore disease and desmin-related myopathy with Mallory body-like inclusions. These disorders constitute the SEPN1 related myopathies (SEPN-RM). On the basis of clinical and laboratory features compatible with SEPN-RM, we performed mutation analysis of SEPN1 in 11 unrelated patients and found one case with pathogenic mutations. He showed early onset axial muscle weakness and developed scoliosis with respiratory insufficiency. Muscle biopsy showed increased variability of fiber size and slight, focal increase of connective tissue. A few fibers showed mini-core changes. SEPN1 mutation analysis revealed that the patient was a compound heterozygote: a previously described insertion (713-714 insA), and a novel nonsense mutation (R439stop).

  • 44.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Fyhr, Ing-Marie
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Structural effects of the slow/b-cardiac myosin heavy chain R453C mutation in cardiac and skeletal muscle2008In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 42, no 2, p. 153-156Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Hypertrophic cardiomyopathy (HCM) represents an important cause of sudden cardiac death particularly in otherwise healthy young individuals. In some families, HCM is caused by distinct mutations of the cardiac beta myosin heavy chain gene (MYH7).

    DESIGN: We have analyzed the expression of the malignant MYH7Arg453Cys mutation, in cardiac and skeletal muscle, and related it to morphological alterations.

    RESULTS: Morphological investigation revealed hypertrophic cardiomyocytes but regularly arranged myofibrils. Skeletal muscle showed no sign of structural alterations.

    CONCLUSIONS: Our results indicate that cardiomyocyte hypertrophy is secondary, due to impaired function, and that the mutation causes no structural alteration in myofibrillar structure in cardiac or skeletal muscle.

  • 45.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Hammans, Simon
    Wessex Neurological Centre, Southampton General Hospital, Southampton, UK.
    Lindberg, Christopher
    Department of Neurology, Institute of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Lossos, Alexander
    Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Clarke, Nigel F.
    Institute for Neuromuscular Research, Children’s Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
    Mazanti, Ingrid
    Cellular Pathology, Southampton General Hospital, Southampton, UK.
    Waddell, Leigh B.
    Institute for Neuromuscular Research, Children’s Hospital at Westmead and Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
    Fellig, Yakov
    Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Foulds, Nicola
    Wessex Clinical Genetics Services, UHS NHS Foundation Trust, Department of Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
    Katifi, Haider
    Wessex Neurological Centre, Southampton General Hospital, Southampton, UK.
    Webster, Richard
    Department of Neurology, Children’s Hospital at Westmead, Sydney, New South Wales, Australia.
    Raheem, Olayinka
    Neuromuscular Research Unit, Tampere University and Hospital, Tampere, Finland.
    Udd, Bjarne
    Neuromuscular Research Unit, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Department of Medical Genetics, Folkhälsan Genetic Institute, Helsinki University, Helsinki, Finland.
    Argov, Zohar
    Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations2014In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, no 6, p. 801-808Article in journal (Refereed)
    Abstract [en]

    Myosin myopathies comprise a group of inherited diseases caused by mutations in myosin heavy chain (MyHC) genes. Homozygous or compound heterozygous truncating MYH2 mutations have been demonstrated to cause recessive myopathy with ophthalmoplegia, mild-to-moderate muscle weakness and complete lack of type 2A muscle fibers. In this study, we describe for the first time the clinical and morphological characteristics of recessive myosin IIa myopathy associated with MYH2 missense mutations. Seven patients of five different families with a myopathy characterized by ophthalmoplegia and mild-to-moderate muscle weakness were investigated. Muscle biopsy was performed to study morphological changes and MyHC isoform expression. Five of the patients were homozygous for MYH2 missense mutations, one patient was compound heterozygous for a missense and a nonsense mutation and one patient was homozygous for a frame-shift MYH2 mutation. Muscle biopsy demonstrated small or absent type 2A muscle fibers and reduced or absent expression of the corresponding MyHC IIa transcript and protein. We conclude that mild muscle weakness and ophthalmoplegia in combination with muscle biopsy demonstrating small or absent type 2A muscle fibers are the hallmark of recessive myopathy associated with MYH2 mutations.

  • 46.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Hilton-Jones, David
    Department of Neurology, West Wing, John Racliffe Hospital, Oxford, UK.
    Raheem, Olayinka
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland.
    Saukkonen, Anna Maija
    Department of Neurology, Central Hospital of Northern Karelia, Joensuu, Finland.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska Hospital, Gothenburg, Sweden.
    Udd, Bjarne
    Neuromuscular Centre, Tampere University and Hospital, Tampere, Finland / Department of Neurology, Vasa Central Hospital, Vasa, Finland / Folkhälsan Genetic Institute, Department of Medical Genetics, Helsinki University, Helsinki, Finland.
    Human disease caused by loss of fast IIa myosin heavy chain due to recessive MYH2 mutations2010In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 133, no 5, p. 1451-1459Article in journal (Refereed)
    Abstract [en]

    Striated muscle myosin heavy chain is a molecular motor protein that converts chemical energy into mechanical force. It is a major determinant of the physiological properties of each of the three muscle fibre types that make up the skeletal muscles. Heterozygous dominant missense mutations in myosin heavy chain genes cause various types of cardiomyopathy and skeletal myopathy, but the effects of myosin heavy chain null mutations in humans have not previously been reported. We have identified the first patients lacking fast type 2A muscle fibres, caused by total absence of fast myosin heavy chain IIa protein due to truncating mutations of the corresponding gene MYH2. Five adult patients, two males and three females, from three unrelated families in UK and Finland were clinically assessed and muscle biopsy was performed in one patient from each family. MYH2 was sequenced and the expression of the corresponding transcripts and protein was analysed in muscle tissue. The patients had early-onset symptoms characterized by mild generalized muscle weakness, extraocular muscle involvement and relatively favourable prognosis. Muscle biopsy revealed myopathic changes including variability of fibre size, internalized nuclei, and increased interstitial connective and adipose tissue. No muscle fibres expressing type IIa myosin heavy chain were identified and the MYH2 transcripts were markedly reduced. All patients were compound heterozygous for truncating mutations in MYH2. The parents were unaffected, consistent with recessive mutations. Our findings show that null mutations in the fast myosin heavy chain IIa gene cause early onset myopathy and demonstrate that this isoform is necessary for normal muscle development and function. The relatively mild phenotype is interesting in relation to the more severe phenotypes generally seen in relation to recessive null mutations in sarcomeric proteins.

  • 47.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden.
    Holmgren, D.
    Division of Pediatric Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, M.
    Department of Pediatrics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Distal arthrogryposis and muscle weakness associated with a beta-tropomyosin mutation2007In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 68, no 10, p. 772-775Article in journal (Refereed)
    Abstract [en]

    Tropomyosin (TM), a sarcomeric thin-filament protein, plays an essential part in muscle contraction by regulating actin-myosin interaction. We describe two patients, a woman and her daughter, with muscle weakness and distal arthrogryposis (DA) type 2B, caused by a heterozygous missense mutation, R133W, in TPM2, the gene encoding beta-TM. Our results demonstrate the involvement of muscle dysfunction in the pathogenesis of DA and the fact that DA2B may be caused by mutations in TPM2.

  • 48.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Kimber, Eva
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Department of Neuropediatrics, Uppsala University Children's Hospital, Uppsala, Sweden.
    Kroksmark, Anna-Karin
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Queen Silvia's Children's Hospital, Göteborg, Sweden.
    Jerre, Ragnar
    Department of Orthopedics, Sahlgrenska University Hospital, Göteborg, Sweden.
    Tulinius, Mar
    Departments of Pediatrics, Institute for Clinical Sciences, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden / Queen Silvia's Children's Hospital, Göteborg, Sweden.
    Oldfors, Anders
    Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Embryonic myosin heavy-chain mutations cause distal arthrogryposis and developmental myosin myopathy that persists postnatally2008In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 8, p. 1083-1090Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myosin is a molecular motor and the essential part of the thick filament of striated muscle. The expression of myosin heavy-chain (MyHC) isoforms is developmentally regulated. The embryonic isoform encoded from MYH3 (OMIM *160720) is expressed during fetal life. Recently, mutations in MYH3 were demonstrated to be associated with congenital joint contractures, that is, Freeman-Sheldon and Sheldon-Hall syndromes, which are both distal arthrogryposis syndromes. Mutations in other MyHC isoforms cause myopathy. It is unknown whether MYH3 mutations cause myopathy because muscle tissue has not been studied.

    OBJECTIVES: To determine whether novel MYH3 mutations are associated with distal arthrogryposis and to demonstrate myopathic changes in muscle biopsy specimens from 4 patients with distal arthrogryposis and MYH3 mutations.

    DESIGN: In a cohort of patients with distal arthrogryposis, we analyzed the entire coding sequence of MYH3. Muscle biopsy specimens were obtained, and in addition to morphologic analysis, the expression of MyHC isoforms was investigated at the protein and transcript levels.

    RESULTS: We identified patients from 3 families with novel MYH3 mutations. These mutations affect developmentally conserved residues that are located in different regions of the adenosine triphosphate-binding pocket of the MyHC head. The embryonic (MYH3) isoform was not detected in any of the muscle biopsy samples, indicating a normal developmental downregulation of MYH3 in these patients. However, morphologic analysis of muscle biopsy specimens from the 4 patients revealed mild and variable myopathic features and a pathologic upregulation of the fetal MyHC isoform (MYH8) in 1 patient.

    CONCLUSIONS: Distal arthrogryposis associated with MYH3 mutations is secondary to myosin myopathy, and postnatal muscle manifestations are variable.

  • 49.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Leren, Trond P.
    Medical Genetics Laboratory, Department of Medical Genetics, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
    Abdul-Hussein, Saba
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Tulinius, Mar
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Brunvand, Leif
    Department of Pediatrics, Ullevål University Hospital, Oslo, Norway.
    Dahl, Hilde M.
    Department of Pediatrics, Ullevål University Hospital, Oslo, Norway.
    Oldfors, Anders
    Department of Pathology, Institute of Biomedicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
    Unexpected myopathy associated with a mutation in MYBPC3 and misplacement of the cardiac myosin binding protein C2010In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 47, no 8, p. 575-577Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myosin binding protein C (MyBPC) is essential for the structure of the sarcomeres in striated muscle. There is one cardiac specific isoform and two skeletal muscle specific isoforms. Mutations in MYBPC3 encoding the cardiac isoform cause cardiomyopathy.

    METHODS AND RESULTS: We have identified an infant with fatal cardiomyopathy due to a homozygous mutation, p.R943X, in MYBPC3. The patient also had an unexpected skeletal myopathy. The patient expressed the cardiac specific MyBPC isoform in skeletal muscle at transcript and protein levels. Numerous muscle fibres expressing the mutant cardiac isoform showed structural abnormalities with disorganisation of sarcomeres and depletion of myosin thick filaments.

    CONCLUSIONS: The surprising identification of a skeletal myopathy in this patient was due to aberrant expression of mutant cardiac MyBPC in skeletal muscle.

  • 50.
    Tajsharghi, Homa
    et al.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ohlsson, M.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Palm, L.
    Department of Paediatrics Malmö, Skåne University Hospital, Malmö, Sweden.
    Oldfors, A.
    Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Myopathies associated with β-tropomyosin mutations2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 11, p. 923-933Article, review/survey (Refereed)
    Abstract [en]

    Mutations in TPM2, encoding β-tropomyosin, have recently been found to cause a range of muscle disorders. We review the clinical and morphological expression of the previously reported mutations illustrating the heterogeneity of β-tropomyosin-associated diseases and describe an additional case with a novel mutation. The manifestations of mutations in TPM2 include non-specific congenital myopathy with type 1 fibre predominance, nemaline myopathy, cap disease and distal arthrogryposis. In addition, Escobar syndrome with nemaline myopathy is a manifestation of homozygous truncating β-tropomyosin mutation. Cap disease appears to be the most common morphological manifestation. A coarse intermyofibrillar network and jagged Z lines are additional frequent changes. The dominant β-tropomyosin mutations manifest either as congenital myopathy or distal arthrogryposis. The various congenital myopathies are usually associated with moderate muscle weakness and no congenital joint contractures. The distal arthrogryposis syndromes associated with TPM2 mutations include the less severe forms, with congenital contractures mainly of the hands and feet and mild or no muscle weakness. The dominant TPM2 mutations include amino acid deletions/insertions and missense mutations. There is no clear relation between the type of mutations or the localisation of the mutated residue in the β-tropomyosin molecule and the clinical and morphological phenotype.

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