Bi-allelic mutations in MYL1 cause a severe congenital myopathy

Hum Mol Genet. 2018 Dec 15;27(24):4263-4272. doi: 10.1093/hmg/ddy320.

Gianina Ravenscroft ¹, Irina T Zaharieva ², Carlo A Bortolotti ³, Matteo Lambrughi ³, Marcello Pignataro ⁴, Marco Borsari ⁴, Caroline A Sewry ², Rahul Phadke ², Goknur Haliloglu ⁴, Royston Ong ¹, Hayley Goullée ¹, Tamieka Whyte ², Uk K Consortium ⁵, Adnan Manzur ², Beril Talim ⁶, Ulkuhan Kaya ⁷, Daniel P S Osborn ⁸, Alistair R R Forrest ¹, Nigel G Laing ¹, Francesco Muntoni ² ⁹

Affiliations

1 Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands WA, Australia.
2 The Dubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
3 Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
4 Department of Chemical and Geological Sciences, University of Modena and Reggio Emilia, Modena, Italy.
5 Wellcome Trust Sanger Institute, Cambridge, UK.
6 Pediatric Pathology Unit, Hacettepe University Children's Hospital, Ankara, Turkey.
7 Department of Pediatric Neurology, Dr. Sami Ulus Maternity and Children's Research and Training Hospital, Ministry of Health, Ankara, Turkey.
8 Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
9 NIHR Great Ormond Street Hospital Biomedical Research Centre, 30 Guilford Street, London WC1N 1EH, UK.

PMID: 30215711 DOI: 10.1093/hmg/ddy320

Abstract

Congenital myopathies are typically characterised by early onset hypotonia, weakness and hallmark features on biopsy. Despite the rapid pace of gene discovery, ∼50% of patients with a congenital myopathy remain without a genetic diagnosis following screening of known disease genes. 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. We identified variants in the gene (MYL1) encoding the skeletal muscle fast-twitch specific Myosin essential light chain (ELC) 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 modelling 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 ELC is critical for myofibre development and function. Our data implicate MYL1 as a crucial protein for adequate skeletal muscle function and that MYL1 deficiency is associated with severe congenital myopathy.

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