Mutations inMYLPFcause a novel segmental amyoplasia that manifests as distal arthrogryposis

Abstract

AbstractWe 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 ofmyosin light chain, phosphorylatable, fast skeletal muscle(MYLPF). In a seventh family, a c.487G>A, p.(Gly163Ser) variant inMYLPFarosede novoin 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 inMYLPFunderlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. 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 zebrafishmylpfa. Themylpfamutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating thatmylpfimpairment most severely affects limb movement.mylpfamutant 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.