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A variant in SMOC2, affecting the interaction with COL9A1, causes autosomal-dominant multiple epiphyseal dysplasia
  • +14
  • Feng Long,
  • Yan Li,
  • Hongbiao Shi,
  • Pengyu Li,
  • Shaoqiang Guo,
  • Yuer Ma,
  • Shijun Wei,
  • Fei Gao,
  • Meitian Wang,
  • Ruonan Duan,
  • Xiaojing Wang,
  • Kun Yang,
  • wenjie Sun,
  • Xi Li,
  • Lin LI,
  • Jiangxia Li,
  • Qiji Liu
Feng Long
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Yan Li
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Hongbiao Shi
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Pengyu Li
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Shaoqiang Guo
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Yuer Ma
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Shijun Wei
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Fei Gao
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Meitian Wang
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Ruonan Duan
Shandong University Qilu Hospital
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Xiaojing Wang
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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Kun Yang
Institute of Basic Medicine, Shandong Academy of Medical Sciences
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wenjie Sun
Shandong University School of Medicine
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Xi Li
Shandong University School of Medicine
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Lin LI
Linyi People's Hospital
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Jiangxia Li
Shandong University School of Medicine
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Qiji Liu
Shandong University School of Medicine
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Abstract

Multiple epiphyseal dysplasia (MED) is a mild osteochondrodysplasia characterized by mild to moderate short stature and early-onset osteoarthritis. In this study, we found a family with MED with no linkage to known pathogenic genes. Whole-exome sequencing revealed a missense mutation (c.1076T>G, p.Leu359Arg, NM_001166412.2) in SPARC-related modular calcium binding 2 (SMOC2). We generated a mouse model by knocking-in the Smoc2 mutation. Mutant mice showed short-limbed dwarfism, disorganized and hypocellular proliferative zones and expanded hypertrophic zones in tibial growth plates. Study of the interaction between MED proteins and SMOC2 showed that SMOC2 and its extracellular calcium-binding (EC) domain could interact with collagen type IX α-1 (COL9A1), however, mutant SMOC2 could not. Our data indicated that SMOC2 mutation is responsible for the MED phenotype. The mutation in SMOC2 affected the interaction between SMOC2 and COL9A1.