Homo sapiens Variation. Homo sapiens

Distal arthrogryposis(DA) is a common congenital hand malformation and isclassified into ten types. The disease-causing gene and pathogenesis of DA islargely uncertain. In our previous study, we recruited a rare four-generationChinese DA-1 family. By using whole-genome exome sequencing, we identified that anovel mutation in MET was responsible for DA-1. However, the specific mechanismof MET predisposing to DA is still unknown. A patient with MET mutation wasfound to have muscle fiber atrophy in distal extremity. Besides, it has beendemonstrated that MET gene plays an important role in myogenesis ofskeletal-muscle-progenitor cells. We hypothesize that METmutation might altermyogenic capacity of skeletal-muscle-progenitor cells. Our pre-experiment showedthat CRISP/Cas9-mediated mutation of MET in mouse recapitulated thecharacteristic of DA. This project intends to explore the mechanism how variant ofX gene predispose to DA by affecting abnormal myogenesis both in vivo and invitro, and discuss the possible relationship between DA muscular deformities and MET function. Eventually, the pathogenesis of DA will be further elucidated.