2. Academic Validation
  3. MET mutation causes muscular dysplasia and arthrogryposis

MET mutation causes muscular dysplasia and arthrogryposis

  • EMBO Mol Med. 2019 Mar;11(3):e9709. doi: 10.15252/emmm.201809709.
Hang Zhou 1 2 3 4,  Chengjie Lian 1 2 3 4,  Tingting Wang 1,  Xiaoming Yang 1,  Caixia Xu 5,  Deying Su 1,  Shuhui Zheng 5,  Xiangyu Huang 6,  Zhiheng Liao 1,  Taifeng Zhou 1,  Xianjian Qiu 7,  Yuyu Chen 1,  Bo Gao 7,  Yongyong Li 5,  Xudong Wang 7,  Guoling You 8,  Qihua Fu 8,  Christina Gurnett 9 10 11,  Dongsheng Huang 7,  Peiqiang Su 12 2 3 4
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Guangdong Province Center for Peripheral Nerve Tissue Engineering and Technology Research, Guangzhou, Guangdong, China.
  • 4 Guangdong Province Engineering Laboratory for Soft Tissue Biofabrication, Guangzhou, Guangdong, China.
  • 5 Research Centre for Translational Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 6 Department of Stomatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
  • 7 Department of Spine Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 8 Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.
  • 10 Department of Neurology, Washington University, St. Louis, MO, USA.
  • 11 Department of Pediatrics, Washington University, St. Louis, MO, USA.
  • 12 Department of Orthopaedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China supq@mail.sysu.edu.cn.
PMID: 30777867 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.

Keywords

MET; arthrogryposis; muscle development; muscular dysplasia; whole‐exome sequence.

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