Högskolan i Skövde

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Högskolan i Skövde, Institutionen för biovetenskap, till och med 2016, därefter Högskolan i Skövde, Institutionen för hälsa och lärande/Institutionen för hälsovetenskaper.

Publications (10 of 61) Show all publications
Maroofian, R., Tajsharghi, H., Ejeskär, K. & Severino, M. (2023). Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders. Brain, 146(12), 5031-5043
Open this publication in new window or tab >>Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
2023 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 12, p. 5031-5043Article in journal (Refereed) Published
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 Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ±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'. 

Keywords
cerebellar atrophy, cerebello-lental degeneration, dystonia, gene transcription, mediator complex, neurodevelopmental disorders, Adolescent, Adult, Atrophy, Cataract, Cerebellum, Child, Child, Preschool, Epilepsy, Epilepsy, Generalized, Female, Humans, Infant, Middle Aged, Movement Disorders, Phenotype, Young Adult, MED27 protein, human, diagnostic imaging, generalized epilepsy, genetics, human, mental disease, motor dysfunction, pathology, preschool child
National Category
Medical Genetics Neurology Pediatrics
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-23471 (URN)10.1093/brain/awad257 (DOI)001106767600001 ()37517035 (PubMedID)2-s2.0-85178648913 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme, 608473Wellcome trust, WT093205MAWellcome trust, WT104033AIAEU, FP7, Seventh Framework Programme, 2012-305121Wellcome trust, 203141/Z/16/Z
Note

CC BY 4.0 DEED

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

Correspondence to: Mariasavina Severino Neuroradiology Unit, IRCCS Istituto Giannina Gaslini Via Gerolamo Gaslini 5, 16147 Genova, GE, Italy E-mail: mariasavinaseverino@gaslini.org

Correspondence may also be addressed to: Reza Maroofian Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology Queen Square, London WC1N 3BG, UK E-mail: r.maroofian@ucl.ac.uk

Part of this research was possible thanks to the Deciphering Developmental Disorders (DDD) study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). R.K. was supported by the European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042). J.R.L. was supported by the National Institute for Neurological Disorders and Stroke Research Program Award R35 NS105078 and the Baylor College of Medicine-GREGoR Program (NHGRI U01 HG001758). H.T. was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. M.A.K. and R.S. were supported by a National Institute for Health Research professorship, Sir Jules Thorn Charitable Trust Award for Biomedical Research and the Rosetrees Trust. This study was also supported by the Wellcome Trust (WT093205MA and WT104033AIA), the Medical Research Council (H.H.), European Union’s Seventh Framework Programme (FP7/2007-2013, under grant agreement no. 2012-305121), the National Institute for Health Research (NIHR), University College London Hospitals (UCLH) and UCLH Biomedical Research Centre (BRC). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The NIHR Oxford Biomedical Research Centre Programme and a Wellcome Trust Core Award (203141/Z/16/Z). P.I. was supported by Foundation for Pediatric Research.

Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2023-12-28Bibliographically approved
Saffari, A., Tajsharghi, H. & Maroofian, R. (2023). The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders. Brain, 146(8), 3273-3288, Article ID awad039.
Open this publication in new window or tab >>The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders
2023 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 8, p. 3273-3288, article id awad039Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
AMC5, NDD, Torsin-1A, arthrogryposis multiplex congenita 5, biallelic variation
National Category
Medical Genetics
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22889 (URN)10.1093/brain/awad039 (DOI)000992679200001 ()36757831 (PubMedID)2-s2.0-85166390254 (Scopus ID)
Funder
German Research Foundation (DFG), SA 4171/1-1, 413543196NIH (National Institutes of Health), R35 NS105078, MDA#512848, 1R01HD104938-01A1EU, FP7, Seventh Framework Programme, 608473Wellcome trust, WT093205MA, WT104033AIA, the Synaptopathies Strategic Award, 165908
Note

CC BY 4.0

Correspondence to: Reza Maroofian

Department of Neuromuscular Diseases, Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK

E-mail: R.Maroofian@ucl.ac.uk

A.S. is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SA 4171/1-1. H.H. is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). S.E. is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1’. This work was supported in part by the US National Institutes of Health R35 NS105078 and MDA#512848 to J.R.L., a jointly funded National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI) grant to the Baylor-Hopkins Center for Mendelian Genomics (UM1 HG006542) and NHGRI Genomics Research to Elucidate Genetics of Rare (BCM-GREGoR U01 HG011758). D.P. is supported by Clinical Research Training Scholarship in Neuromuscular Disease partnered by the American Brain Foundation (ABF) and Muscle Study Group (MSG). The research conducted at the Murdoch Children’s Research Institute was supported by the Victorian Government’s Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to J.C. is generously supported by The Royal Children’s Hospital Foundation. H.T. has been supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement no. 608473. H.S.D. is supported by the Cologne Clinician Scientist Program/Faculty of Medicine/University of Cologne and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project No. 413543196). H.J. has been supported by a grant from the European Union (H2020- MSCA-ITN-2017). A.M.D. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (grant 1R01HD104938-01A1). H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This research was funded in part by the Wellcome Trust (WT093205MA, WT104033AIA and the Synaptopathies Strategic Award, 165908) as well as the Medical Research Council (MRC) (MR/S01165X/1, MR/ S005021/1, G0601943). Additonally, we are grateful for funding from The MSA Trust, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, The Michael J Fox Foundation (MJFF), BBSRC, The Fidelity Trust, Rosetrees Trust, Ataxia UK, Brain Research UK, Sparks GOSH Charity, Alzheimer’s Research UK (ARUK) and CureDRPLA.

Available from: 2023-06-30 Created: 2023-06-30 Last updated: 2023-08-15Bibliographically approved
Rosenhahn, E., O'Brien, T. J., Zaki, M. S., Sorge, I., Wieczorek, D., Rostasy, K., . . . Platzer, K. (2022). Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications. American Journal of Human Genetics, 109(8), 1421-1435
Open this publication in new window or tab >>Bi-allelic loss-of-function variants in PPFIBP1 cause a neurodevelopmental disorder with microcephaly, epilepsy, and periventricular calcifications
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2022 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, no 8, p. 1421-1435Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Cell Press, 2022
Keywords
Acetylcholinesterase, Animals, Drosophila melanogaster, Epilepsy, Loss of Heterozygosity, Microcephaly, Nervous System Malformations, Neurodevelopmental Disorders, Pedigree, animal, genetics, heterozygosity loss, mental disease, nervous system malformation
National Category
Medical Genetics Clinical Laboratory Medicine Neurology Biomedical Laboratory Science/Technology Cell and Molecular Biology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-21694 (URN)10.1016/j.ajhg.2022.06.008 (DOI)000850681500006 ()35830857 (PubMedID)2-s2.0-85135598374 (Scopus ID)
Funder
EU, European Research Council, 714853
Note

CC BY 4.0

© 2022 The Authors

Correspondence: andre.brown@lms.mrc.ac.uk (A.E.X.B.), konrad.platzer@medizin.uni-leipzig.de (K.P.)

We thank all families that participated in this study. This project has received funding from the European Research Council under the European External Action Service Horizon 2020 Research and Innovation Program (grant agreement no. 714853) and was supported by the Medical Research Council through grant MC-A658-5TY30. H.T. was supported by the European External Action Service Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 608473.

Available from: 2022-08-18 Created: 2022-08-18 Last updated: 2022-10-17Bibliographically approved
Calame, D. G., Tajsharghi, H. & Lupski, J. R. (2022). Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia. Annals of Neurology, 92(2), 304-321
Open this publication in new window or tab >>Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia
2022 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 92, no 2, p. 304-321Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Neurology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-21219 (URN)10.1002/ana.26381 (DOI)000800862800001 ()35471564 (PubMedID)2-s2.0-85130695472 (Scopus ID)
Note

Wiley

© 2022 American Neurological Association

First published: 26 April 2022

Available from: 2022-06-10 Created: 2022-06-10 Last updated: 2022-08-15Bibliographically approved
Pagnamenta, A. T., Diaz-Gonzalez, F., Banos-Pinero, B., Ferla, M. P., Toosi, M. B., Calder, A. D., . . . Taylor, J. C. (2022). Variable skeletal phenotypes associated with biallelic variants in PRKG2. Journal of Medical Genetics, 59(10), 947-950
Open this publication in new window or tab >>Variable skeletal phenotypes associated with biallelic variants in PRKG2
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2022 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 59, no 10, p. 947-950Article in journal (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2022
Keywords
Genetics (clinical), Genetics
National Category
Medical Genetics
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-20732 (URN)10.1136/jmedgenet-2021-108027 (DOI)000839164900001 ()34782440 (PubMedID)2-s2.0-85139374485 (Scopus ID)
Funder
Wellcome trust, 203141/Z/16/ZEU, FP7, Seventh Framework Programme, 608473
Note

CC BY 4.0

Published Online First: 15 November 2021

Brief communication

The Genomics England Research Consortium

Correspondence to Dr Deborah Shears; debbie.shears@ouh.nhs.uk Dr Jenny C Taylor; jenny@well.ox.ac.uk

Available from: 2021-11-30 Created: 2021-11-30 Last updated: 2022-10-18Bibliographically approved
Pagnamenta, A. T., Tajsharghi, H. & Houlden, H. (2021). An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. Brain, 144(2), 584-600
Open this publication in new window or tab >>An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
2021 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 144, no 2, p. 584-600Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2021
Keywords
hereditary motor and sensory neuropathies, nerve conduction studies, EMG, genetics: neuropathy, whole-genome sequencing
National Category
Neurosciences Health Sciences
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19776 (URN)10.1093/brain/awaa420 (DOI)000880372000033 ()33559681 (PubMedID)2-s2.0-85102905606 (Scopus ID)
Note

CC BY 4.0

Correspondence to: Henry Houlden, MD, PhD Department of Neuromuscular Disorders, UCL Institute of Neurology WC1N 3BG, UK E-mail: h.houlden@ucl.ac.uk

Genomics England Research Consortium

Available from: 2021-06-10 Created: 2021-06-10 Last updated: 2024-01-16Bibliographically approved
Osborn, D. P., Emrahi, L., Clayton, J., Tabrizi, M. T., Wan, A. Y., Maroofian, R., . . . Tajsharghi, H. (2021). Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3. Genetics in Medicine, 23(4), 787-792
Open this publication in new window or tab >>Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3
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2021 (English)In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 23, no 4, p. 787-792Article in journal (Refereed) Published
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>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>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>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>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. 

Place, publisher, year, edition, pages
Springer, 2021
National Category
Medical Genetics Cardiac and Cardiovascular Systems Health Sciences
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19331 (URN)10.1038/s41436-020-01028-2 (DOI)000598999000001 ()33288880 (PubMedID)2-s2.0-85097242733 (Scopus ID)
Note

CC BY-NC-ND 4.0 "Brief communication"

Available from: 2020-12-17 Created: 2020-12-17 Last updated: 2021-04-23Bibliographically approved
Chatron, N., Becker, F., Morsy, H., Schmidts, M., Hardies, K., Tuysuz, B., . . . Tajsharghi, H. (2020). Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy. Brain, 143(5), 1447-1461
Open this publication in new window or tab >>Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy
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2020 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 143, no 5, p. 1447-1461Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2020
Keywords
arthrogryposis, cleft palate, GAD1, hypsarrhythmia, omphalocele, suppression-burst
National Category
Medical Genetics Neurosciences
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-18483 (URN)10.1093/brain/awaa085 (DOI)000541777000026 ()32282878 (PubMedID)2-s2.0-85085158143 (Scopus ID)
Note

[Additional authors/contributors from:] EuroEpinomics-RES consortium AR working group [see article appendix]

Available from: 2020-06-05 Created: 2020-06-05 Last updated: 2020-08-31
Dahl-Halvarsson, M., Olive, M., Pokrzywa, M., Norum, M., Ejeskär, K. & Tajsharghi, H. (2020). Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase. Disease Models and Mechanisms, 13(12), Article ID dmm047886.
Open this publication in new window or tab >>Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase
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2020 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 13, no 12, article id dmm047886Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
The Company of Biologists Ltd., 2020
Keywords
Drosophila model, E3 ubiquitin ligase, MYH7, Myosin storage myopathy, Potential therapeutic approach, Slow/ß-cardiac myosin heavy chain, Ubiquitin proteasome system
National Category
Neurology Cell and Molecular Biology Biochemistry and Molecular Biology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19335 (URN)10.1242/dmm.047886 (DOI)000607134600003 ()33234710 (PubMedID)2-s2.0-85099172643 (Scopus ID)
Note

CC BY 4.0

Available from: 2020-12-17 Created: 2020-12-17 Last updated: 2021-03-30Bibliographically approved
Trindade, F., Saraiva, F., Keane, S., Leite-Moreira, A., Vitorino, R., Tajsharghi, H. & Falcão-Pires, I. (2020). Preoperative myocardial expression of E3 ubiquitin ligases in aortic stenosis patients undergoing valve replacement and their association to postoperative hypertrophy. PLOS ONE, 15(9), Article ID e0237000.
Open this publication in new window or tab >>Preoperative myocardial expression of E3 ubiquitin ligases in aortic stenosis patients undergoing valve replacement and their association to postoperative hypertrophy
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2020 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 15, no 9, article id e0237000Article in journal (Refereed) Published
Abstract [en]

Currently, aortic valve replacement is the only treatment capable of relieving left ventricle pressure overload in patients with severe aortic stenosis. It aims to improve cardiac function and revert hypertrophy, by triggering myocardial reverse remodeling. Despite immediately relieving afterload, reverse remodeling turns out to be extremely variable. Among other factors, the extent of reverse remodeling may depend on how well ubiquitin-proteasome system tackle hypertrophy. Therefore, we assessed tagged ubiquitin and ubiquitin ligases in the left ventricle collected from patients undergoing valve replacement and tested their association to the degree of reverse remodeling. Patients were classified according to the regression of left ventricle mass (ΔLVM) and assigned to complete (ΔLVM≥15%) or incomplete (ΔLVM≤5%) reverse remodeling groups. No direct inter-group differences were observed. Nevertheless, correlation analysis supports a fundamental role of the ubiquitin-proteasome system during reverse remodeling. Indeed, total protein ubiquitination was associated to hypertrophic indexes such as interventricular septal thickness (r = 0.55, p = 0.03) and posterior wall thickness (r = 0.65, p = 0.009). No significant correlations were observed for Muscle Ring Finger 3. Surprisingly, though, higher levels of atrogin-1 were associated to postoperative interventricular septal thickness (r = 0.71, p = 0.005). In turn, Muscle Ring Finger 1 correlated negatively with this postoperative hypertrophy marker (r = -0.68, p = 0.005), suggesting a cardioprotective role during reverse remodeling. No significant correlations were found with left ventricle mass regression, although a trend for a negative association between the ligase Murine Double Minute 2 and mass regression (r = -0.44, p = 0.10) was found. Animal studies will be necessary to understand whether this ligase is protective or detrimental. Herein, we show, for the first time, an association between the preoperative myocardial levels of ubiquitin ligases and postoperative hypertrophy, highlighting the therapeutic potential of targeting ubiquitin ligases in incomplete reverse remodeling.

Place, publisher, year, edition, pages
PLOS, 2020
National Category
Cardiac and Cardiovascular Systems Other Medical Sciences
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19144 (URN)10.1371/journal.pone.0237000 (DOI)000573851100068 ()32946439 (PubMedID)2-s2.0-85091324224 (Scopus ID)
Note

CC BY 4.0

Available from: 2020-10-01 Created: 2020-10-01 Last updated: 2021-06-14Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8854-5213

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