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Dahl-Halvarsson, M., Olive, M., Pokrzywa, M., Ejeskär, K., Palmer, R. H., Uv, A. E. & Tajsharghi, H. (2018). Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member. Proceedings of the National Academy of Sciences of the United States of America, 115(28), E6566-E6575
Open this publication in new window or tab >>Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member
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2018 (English)In: 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) Published
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.

National Category
Genetics Neurology
Research subject
Biomedical Genetics
Identifiers
urn:nbn:se:his:diva-15878 (URN)10.1073/pnas.1800727115 (DOI)000438050900023 ()29946036 (PubMedID)2-s2.0-85049855441 (Scopus ID)
Available from: 2018-06-29 Created: 2018-06-29 Last updated: 2018-08-30Bibliographically approved
Nilipour, Y., Nafissi, S., Tjust, A. E., Ravenscroft, G., Hossein-Nejad Nedai, H., Taylor, R. L., . . . Tajsharghi, H. (2018). Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies. European Journal of Neurology, 25(6), 841-847
Open this publication in new window or tab >>Ryanodine receptor type 3 (RYR3) as a novel gene associated with a myopathy with nemaline bodies
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2018 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 25, no 6, p. 841-847Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Blackwell Publishing, 2018
Keywords
RYR3, intracellular Ca2+ channels, nemaline myopathy, ryanodine receptors
National Category
Medical and Health Sciences Genetics Medical Genetics Neurology
Research subject
Biomedical Genetics; Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-14955 (URN)10.1111/ene.13607 (DOI)000431989200012 ()29498452 (PubMedID)2-s2.0-85044433098 (Scopus ID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2018-03-12 Created: 2018-03-12 Last updated: 2018-09-25Bibliographically approved
Dahl-Halvarsson, M., Pokrzywa, M., Rauthan, M., Pilon, M. & Tajsharghi, H. (2017). Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells. PLoS ONE, 12(1), Article ID e0170613.
Open this publication in new window or tab >>Myosin Storage Myopathy in C. elegans and Human Cultured Muscle Cells
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0170613Article in journal (Refereed) Published
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.

National Category
Medical Biotechnology Basic Medicine
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-13464 (URN)10.1371/journal.pone.0170613 (DOI)000396176100086 ()28125727 (PubMedID)2-s2.0-85010877212 (Scopus ID)
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2018-01-13Bibliographically approved
Kariminejad, A., Dahl-Halvarsson, M., Ravenscroft, G., Afroozan, F., Keshavarz, E., Goullée, H., . . . Tajsharghi, H. (2017). TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor. Brain, 140(11), 2851-2859
Open this publication in new window or tab >>TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor
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2017 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 140, no 11, p. 2851-2859Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Oxford University Press, 2017
Keywords
TOR1A, endoplasmic reticulum luminal protein torsinA, DYT1 dystonia, TOR1A p.Glu303del, severe arthrogryposis
National Category
Clinical Medicine
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-14154 (URN)10.1093/brain/awx230 (DOI)000414357800017 ()29053766 (PubMedID)2-s2.0-85034765470 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 608473MoRe Research, 608473Swedish Research Council
Available from: 2017-09-25 Created: 2017-09-25 Last updated: 2018-02-27Bibliographically approved
Kariminejad, A., Ghaderi-Sohi, S., Hossein-Nejad Nedai, H., Varasteh, V., Moslemi, A.-R. & Tajsharghi, H. (2016). Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum. BMC Musculoskeletal Disorders, 17(1), 1-5, Article ID 109.
Open this publication in new window or tab >>Lethal multiple pterygium syndrome, the extreme end of the RYR1 spectrum
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2016 (English)In: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 17, no 1, p. 1-5, article id 109Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
Lethal multiple pterygium syndrome, Akinesia, Arthrogryposis, Foetal hydrops, Cystic hygroma, Ryanodine receptor 1, RYR1
National Category
Medical Genetics
Identifiers
urn:nbn:se:his:diva-12050 (URN)10.1186/s12891-016-0947-5 (DOI)000371387600001 ()26932181 (PubMedID)2-s2.0-84959363680 (Scopus ID)
Available from: 2016-03-18 Created: 2016-03-18 Last updated: 2018-01-10Bibliographically approved
Kariminejad, A., Almadani, N., Khoshaeen, A., Olsson, B., Moslemi, A.-R. & Tajsharghi, H. (2016). Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome. BMC Genetics, 17(1), Article ID 71.
Open this publication in new window or tab >>Truncating CHRNG mutations associated with interfamilial variability of the severity of the Escobar variant of multiple pterygium syndrome
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2016 (English)In: BMC Genetics, ISSN 1471-2156, E-ISSN 1471-2156, Vol. 17, no 1, article id 71Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2016
Keywords
severe genetic disorder
National Category
Clinical Medicine
Research subject
Medical sciences; Bioinformatics; Biomedical Genetics
Identifiers
urn:nbn:se:his:diva-12337 (URN)10.1186/s12863-016-0382-5 (DOI)000377077500001 ()27245440 (PubMedID)2-s2.0-84971537060 (Scopus ID)
Funder
Swedish Research Council
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2018-07-31Bibliographically approved
Pokrzywa, M., Norum, M., Lengqvist, J., Ghobadpour, M., Abdul-Hussein, S., Moslemi, A.-R. & Tajsharghi, H. (2015). Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC. PLoS ONE, 10(11), Article ID e0142094.
Open this publication in new window or tab >>Developmental MYH3 Myopathy Associated with Expression of Mutant Protein and Reduced Expression Levels of Embryonic MyHC
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142094Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library Science, 2015
Keywords
myosin heavy-chain, skeletal muscle, IIB-myosin, in-vivo, gene, mutations, hypertrophy, atrophy, mouse, mice
National Category
Clinical Medicine
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-11762 (URN)10.1371/journal.pone.0142094 (DOI)000364398700080 ()26544689 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-12-16 Created: 2015-12-16 Last updated: 2017-12-01Bibliographically approved
Olivé, M., Abdul-Hussein, S., Oldfors, A., González-Costello, J., van der Ven, P. F. M., Fürst, D. O., . . . Tajsharghi, H. (2015). New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations. Human Molecular Genetics, 24(13), 3638-3650, Article ID 108.
Open this publication in new window or tab >>New cardiac and skeletal protein aggregate myopathy associated with combined MuRF1 and MuRF3 mutations
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 13, p. 3638-3650, article id 108Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2015
Keywords
Protein, aggregate, myopathies
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:his:diva-11009 (URN)10.1093/hmg/ddv108 (DOI)000357523900004 ()25801283 (PubMedID)2-s2.0-84936766476 (Scopus ID)
Available from: 2015-06-11 Created: 2015-06-08 Last updated: 2017-11-27Bibliographically approved
Olivé, M., Abdul-Hussein, S., Oldfors, A., González-Costello, J., van der Ven, P. F. M., Fürst, D. O., . . . Tajsharghi, H. (2015). 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]. Human Molecular Genetics, 24(21), 6264-6264
Open this publication in new window or tab >>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]
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 21, p. 6264-6264Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Oxford University Press, 2015
National Category
Neurology
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-11987 (URN)10.1093/hmg/ddv311 (DOI)000363024000025 ()26345447 (PubMedID)2-s2.0-84949188726 (Scopus ID)
Available from: 2016-02-26 Created: 2016-02-26 Last updated: 2017-11-30Bibliographically approved
Tajsharghi, H., Hammans, S., Lindberg, C., Lossos, A., Clarke, N. F., Mazanti, I., . . . Oldfors, A. (2014). Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations. European Journal of Human Genetics, 22(6), 801-808
Open this publication in new window or tab >>Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations
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2014 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, no 6, p. 801-808Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
Myosin heavy chain, MYH2, ophthalmoplegia, myosin myopathy
National Category
Neurology
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-11950 (URN)10.1038/ejhg.2013.250 (DOI)000336496800013 ()24193343 (PubMedID)2-s2.0-84901056079 (Scopus ID)
Available from: 2016-02-25 Created: 2016-02-25 Last updated: 2017-11-30Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8854-5213

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