Bi-allelic mutations in MYL1 cause a severe congenital myopathy
| العنوان: | Bi-allelic mutations in MYL1 cause a severe congenital myopathy |
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| المؤلفون: | Gianina, Ravenscroft, Irina T, Zaharieva, Carlo A, Bortolotti, Matteo, Lambrughi, Marcello, Pignataro, Marco, Borsari, Caroline A, Sewry, Rahul, Phadke, Goknur, Haliloglu, Royston, Ong, Hayley, Goullée, Tamieka, Whyte, Uk K, Consortium, Adnan, Manzur, Beril, Talim, Ulkuhan, Kaya, Daniel P S, Osborn, Alistair R R, Forrest, Nigel G, Laing, Francesco, Muntoni |
| المصدر: | Human Molecular Genetics. |
| بيانات النشر: | Oxford University Press (OUP), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Myosin Light Chains, Muscle Hypotonia, Myosin light-chain kinase, Myotonia Congenita, Biology, Alleles, Animals, Consanguinity, Disease Models, Animal, Exome, Homozygote, Humans, Muscle, Skeletal, Mutation, Myosin Heavy Chains, Pedigree, Zebrafish, 03 medical and health sciences, Internal medicine, Myosin, Genetics, medicine, Molecular Biology, Genetics (clinical), Muscle biopsy, medicine.diagnostic_test, Animal, Myotonia congenita, Skeletal muscle, Skeletal, General Medicine, medicine.disease, Congenital myopathy, Hypotonia, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Disease Models, Muscle, General Article, medicine.symptom |
| الوصف: | OBJECTIVE: Congenital myopathies are typically characterised by early onset hypotonia, weakness and hallmark features on biopsy. Despite the rapid pace of gene discovery, approximately 50% of patients with a congenital myopathy remain without a genetic diagnosis following screening of known disease genes. METHODS: We performed exome sequencing on two consanguineous probands diagnosed with a congenital myopathy and muscle biopsy showing selective atrophy/hypotrophy or absence of type II myofibres. RESULTS: We identified variants in the gene (MYL1) encoding the skeletal muscle fast-twitch specific myosin essential light chain in both probands. A homozygous essential splice acceptor variant (c.479-2A>G, predicted to result in skipping of exon 5 was identified in Proband 1, and a homozygous missense substitution (c.488T>G, p.(Met163Arg)) was identified in Proband 2. Protein modeling of the p.(Met163Arg) substitution predicted it might impede intermolecular interactions that facilitate binding to the IQ domain of myosin heavy chain, thus likely impacting on the structure and functioning of the myosin motor. MYL1 was markedly reduced in skeletal muscle from both probands, suggesting that the missense substitution likely results in an unstable protein. Knock down of myl1 in zebrafish resulted in abnormal morphology, disrupted muscle structure and impaired touch-evoked escape responses, thus confirming that skeletal muscle fast-twitch specific myosin essential light chain is critical for myofibre development and function. INTERPRETATION: Our data implicate MYL1 as a crucial protein for adequate skeletal muscle function and that MYL1 deficiency is associated with a severe congenital myopathy. |
| وصف الملف: | application/pdf |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::96f1bd94d9090c98cd1087064a4664c4Test https://doi.org/10.1093/hmg/ddy320Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....96f1bd94d9090c98cd1087064a4664c4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
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