Mutations in mylpf cause a novel segmental amyoplasia that manifests as distal arthrogryposis

Radhakrishnan, Periyasamy and Girisha, KM and Nayak, Shalini S and Shukla, Anju (2020) Mutations in mylpf cause a novel segmental amyoplasia that manifests as distal arthrogryposis. The American Journal of Human Genetics, 107. pp. 1-18. ISSN 0002-9297

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We identified ten persons in six consanguineous families with distal arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T [p.Cys157Phe] or c.469T>C [p.Cys157Arg]) affecting the same residue of myosin light chain, phosphorylatable, fast skeletal muscle (MYLPF). In a seventh family, a c.487G>A (p.Gly163Ser) variant in MYLPF arose de novo in a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly inherited DA, a c.98C>T (p.Ala33Val) variant segregated in all four persons tested. Variants in MYLPF underlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associ�ated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this inter�action. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demon�strating that mylpf impairment most severely affects limb movement. mylpfa mutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.

Item Type: Article
Subjects: Medicine > KMC Manipal > Paediatrics
Depositing User: KMC Library
Date Deposited: 15 Oct 2020 04:13
Last Modified: 15 Oct 2020 04:13

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