MET mutation causes muscular dysplasia and arthrogryposis
MET mutation causes muscular dysplasia and arthrogryposis
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MET突变导致肌肉发育不良和关节挛缩
DOI：
10.15252/emmm.201809709
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发表时间：
2019-03-01
影响因子：
11.1
通讯作者：
Su, Peiqiang
中科院分区：
文献类型：
--
作者：
Zhou, Hang;Lian, Chengjie;Su, Peiqiang
关节退缩症是一组表型和遗传异质性疾病，其特征是身体两个或多个部位的先天性肌挛缩，其发病机制和致病基因尚不清楚。我们研究了一个四代关节旋转畸形家系，其特征是弓指畸形，前臂旋后受限，前臂和手部肌纤维丢失。通过全外显子组测序，我们证实该家系中存在与P.Y1234C突变相关的关节融合。MET p.Y1234C突变导致MET酪氨酸激酶激活失败。建立了Met p.Y1232C突变小鼠模型。纯合子小鼠的表型包括胚胎致死性和来自迁徙前体的肌肉完全丧失。杂合子小鼠活着出生，并显示出阑尾肌和轴肌中肌纤维的数量减少。肌祖细胞的缺陷迁移和次级成肌细胞的增殖受损被证明是突变小鼠骨骼肌发育不良的原因。总体而言，我们的研究表明，MET是关节紊乱病的致病基因，MET突变可能导致人类骨骼肌发育不良。
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.