MET mutation causes muscular dysplasia andarthrogryposis.

Hang Zhou,Bo Gao,Xudong Wang,Xiaoming Yang,Taifeng Zhou,Dongsheng Huang,Zhiheng Liao,Yongyong Li,Peiqiang Su,Guoling You,Tingting Wang,Chengjie Lian,Xianjian Qiu,Caixia Xu,Xiangyu Huang,Deying Su,Yuyu Chen,Qin Fu ,Shunyi Zheng ,Christina A Gurnett

doi:10.15252/emmm.201809709

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.

Highlights

Arthrogryposis is a group of disorders characterized by congenital joint contractures that mainly involve two or more areas of the body (Bamshad et al, 2009; Bayram et al, 2016) and affects approximately 1 in 3,000 newborns (Bayram et al, 2016)
In vitro study showed that MET p.Y1234C mutation resulted in the failure of phosphorylation and loss of tyrosine kinase activity of MET receptor
A Met p.Y1232C transgenic mouse model was established, and defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were detected, which was in accordance with previous study (Maina et al, 1996)

Summary

Introduction

Arthrogryposis is a group of disorders characterized by congenital joint contractures that mainly involve two or more areas of the body (Bamshad et al, 2009; Bayram et al, 2016) and affects approximately 1 in 3,000 newborns (Bayram et al, 2016). Arthrogryposis is a group of disorders with high clinical and genetic heterogeneity. Variants in more than 220 genes have been found to be associated with arthrogryposis (Narkis et al, 2007; Drury et al, 2014; Hunter et al, 2015; Bayram et al, 2016). The molecular etiology still remains unclear in a large number of cases of arthrogryposis. Further studies to identify causative genes and pathogenic mechanisms are needed

Methods

Results

Conclusion