MET mutation causes muscular dysplasia and arthrogryposis

Abstract

Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.

Two nonsense GLI3 variants are associated with polydactyly and syndactyly in two families by affecting the sonic hedgehog signaling pathway

“…In Family 2, IV:2, III:10, and III:11 were subjected to whole‐exome sequencing. As previously reported (Zhou et al, 2019), we annotated and filtered variants and kept variants that were novel in dbSNP. Polyphen‐2, Mutation Taster, and Genomic Evolutionary Rate Profiling (GERP) were then used to predict the potential functional effects of these mutations.…”

MET is a new confirmed gene responsible for familial distal arthrogryposis

“…The affected residue is adjacent to the tyrosine mutated in the previously reported Chinese family (Zhou et al, 2019 ). Functional studies on MET p.Y1234 mutation showed the inability of the mutant MET receptor to phosphorylate residues Y-1234/1235, Y-1349, and Y-1356 in response to HGF treatment, resulting in failure of c-MET activation and decreasing of its kinase activity, with the consequent impairment of the HGF-MET signaling (Zhou et al, 2019 ). A similar pathogenic mechanism is then anticipated for the mutation identified in our family.…”

“…In 2019, a study reported a single four-generation Chinese family with arthrogryposis with only upper limb involvement and a missense mutation of the MET gene affecting the Tyrosine residue 1234 (p.Tyr1234Cys) (Zhou et al, 2019 ). The authors generated a Met p.Y1232C (corresponding to the p.Y1234C in humans) transgenic mouse model identifying a defective migration of muscle progenitor cells and an impaired proliferation of secondary myoblasts.…”