Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis

Am J Hum Genet. 2020 Aug 6;107(2):293-310. doi: 10.1016/j.ajhg.2020.06.014. Epub 2020 Jul 23.


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.

Keywords: Mendelian disease; amyoplasia; congenital contractures; development; distal arthrogryposis; exome sequencing; myosin; skeletal muscle; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Animals
  • Arthrogryposis / genetics*
  • Child
  • Contracture / genetics
  • Extremities / pathology
  • Female
  • Humans
  • Male
  • Muscle, Skeletal / pathology*
  • Musculoskeletal Abnormalities / genetics*
  • Mutation / genetics*
  • Myosin Light Chains / genetics*
  • Myosins / genetics
  • Pedigree
  • Young Adult
  • Zebrafish / genetics


  • Myosin Light Chains
  • Myosins