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A variant in SMOC2, inhibiting BMP signaling by competitively binding to BMPR1B, causes multiple epiphyseal dysplasia

By Feng Long, Lin Li, Hongbiao Shi, Pengyu Li, Shaoqiang Guo, Yuer Ma, Yan Li, Shijun Wei, Fei Gao, Shang Gao, Meitian Wang, Ruonan Duan, Xiaojing Wang, Kun Yang, Ai Liu, Anran Wang, Xiao Chen, Wenjie Sun, Xi Li, Jiangxia Li, Qiji Liu

Posted 28 Jan 2020
bioRxiv DOI: 10.1101/2020.01.27.921825

Previously study showed that SMOC, a matricellular protein, inhibits BMP signaling downstream of its receptor via activation of mitogen-activated protein kinase (MAPK) signaling. In our study, exome sequencing revealed a missense mutation (c.1076T>G, p.Leu359Arg) in EC domain of SMOC2 in a Chinese family with multiple epiphyseal disease (MED). The pathogenicity of this SMOC2 variant was verified by Smoc2L359R/L359R knock-in mice. Of note, decreasing phosphorylation of SMAD1/5/9 was detected in growth plates and primary chondrocytes from Smoc2L359R/L359R mice. Furthermore, binding affinity of mutant SMOC2 with collagen IX and HSPG in the extracellular matrix of cartilage were reduced while binding affinity with BMPRIB was intact. In addition, in contrast to previously results, that SMOC2 cannot antagonize BMP activity in the presence of a constitutively activated BMP receptor. These results support that SMOC2 with p.Leu359Arg variant act as an antagonist of canonical BMP pathway by competitively binding with BMP receptors.

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