PUBLICATION
Bi-allelic mutations in MYL1 cause a severe congenital myopathy
- Authors
- Ravenscroft, G., Zaharieva, I., Bortolotti, C.A., Lambrughi, M., Pignataro, M., Borsari, M., Sewry, C.A., Phadke, R., Haliloglu, G., Ong, R., Goullée, H., Whyte, T., UK10K Consortium, Manzur, A., Talim, B., Kaya, U., Osborn, D.P., Forrest, A., Laing, N.G., Muntoni, F.
- ID
- ZDB-PUB-180915-5
- Date
- 2018
- Source
- Human molecular genetics 27(24): 4263-4272 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Alleles
- Animals
- Consanguinity
- Disease Models, Animal
- Exome/genetics
- Homozygote
- Humans
- Male
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/physiopathology*
- Mutation
- Myosin Heavy Chains/genetics
- Myosin Light Chains/genetics*
- Myotonia Congenita/genetics*
- Myotonia Congenita/physiopathology
- Pedigree
- Zebrafish/genetics
- PubMed
- 30215711 Full text @ Hum. Mol. Genet.
Citation
Ravenscroft, G., Zaharieva, I., Bortolotti, C.A., Lambrughi, M., Pignataro, M., Borsari, M., Sewry, C.A., Phadke, R., Haliloglu, G., Ong, R., Goullée, H., Whyte, T., UK10K Consortium, Manzur, A., Talim, B., Kaya, U., Osborn, D.P., Forrest, A., Laing, N.G., Muntoni, F. (2018) Bi-allelic mutations in MYL1 cause a severe congenital myopathy. Human molecular genetics. 27(24):4263-4272.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping