biostudies-literatureChong JXNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of Neurological Disorders and StrokeEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD NIH HHSNHLBI NIH HHSNational Heart, Lung, and Blood InstituteNational Institute of General Medical SciencesNational Human Genome Research InstituteNHGRI NIH HHSNINDS NIH HHSNIAMS NIH HHSNIGMS NIH HHSNIH HHS293-310https://www.ebi.ac.uk/biostudies/studies/S-EPMC7413889biostudies-literatureUnknown107(2)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 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 zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating 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.American journal of human geneticsMutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.PMC7413889R01 GM088041R01 GM117964S10 OD021553P30 NS045758P30 NS104177R01 HD048895UM1 HG006493S10 OD010383R01 AR067279U24 HG008956T32 NS077984R01 HL150953Talbot JCBuckingham KJCapri YGirisha KMNayak SSUniversity of Washington Center for Mendelian GenomicsSaadeh-Haddad RMor-Shaked HChong JXMarvin CTRadhakrishnan PInzana FTeets EMPrevis SBen-Omran TAl-Mulla MDieterich KRendu JAylsworth ASShukla AShively KMHarel TNickerson DAWarshaw DMJanssen PMLAmacher SLSchatz UABamshad MJLatypova XMartin BLFaure JAlmusafri FfalseMutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.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 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 zebrafish mylpfa. The mylpfa mutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating 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.2020-01-01T00:00:00Z2020 Aug2024-10-15T23:21:00.862Z2021-02-21T07:23:29ZS-EPMC74138893270708710.1016/j.ajhg.2020.06.014