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

TitleMutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis.
Publication TypeJournal Article
Year of Publication2020
AuthorsChong, JX, Talbot, JC, Teets, EM, Previs, S, Martin, BL, Shively, KM, Marvin, CT, Aylsworth, AS, Saadeh-Haddad, R, Schatz, UA, Inzana, F, Ben-Omran, T, Almusafri, F, Al-Mulla, M, Buckingham, KJ, Harel, T, Mor-Shaked, H, Radhakrishnan, P, Girisha, KM, Nayak, SS, Shukla, A, Dieterich, K, Faure, J, Rendu, J, Capri, Y, Latypova, X, Nickerson, DA, Warshaw, DM, Janssen, PML, Amacher, SL, Bamshad, MJ
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Volume107
Issue2
Pagination293-310
Date Published2020 08 06
ISSN1537-6605
Abstract

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.

DOI10.1016/j.ajhg.2020.06.014
PubMed ID32707087
PubMed Central IDPMC7413889
Grant ListR01 HL150953 / HL / NHLBI NIH HHS / United States
P30 NS045758 / NS / NINDS NIH HHS / United States
R01 GM088041 / GM / NIGMS NIH HHS / United States
P30 NS104177 / NS / NINDS NIH HHS / United States
S10 OD021553 / OD / NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
T32 NS077984 / NS / NINDS NIH HHS / United States
S10 OD010383 / OD / NIH HHS / United States
R01 HD048895 / HD / NICHD NIH HHS / United States
R01 GM117964 / GM / NIGMS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 AR067279 / AR / NIAMS NIH HHS / United States