Gui Baoheng, Yu Chenxi, Li Xiaoxin, Zhao Sen, Zhao Hengqiang, Yan Zihui, Cheng Xi, Lin Jiachen, Zheng Haiyang, Shao Jiashen, Zhao Zhengye, Zhao Lina, Niu Yuchen, Zhao Zhi, Wang Huizi, Xie Bobo, Wei Xianda, Gui Chunrong, Li Chuan, Chen Shaoke, Wang Yi, Song Yanning, Gong Chunxiu, Zhang Terry Jianguo, Fan Xin, Wu Zhihong, Chen Yujun, Wu Nan
Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
Front Cell Dev Biol. 2021 Apr 14;9:661747. doi: 10.3389/fcell.2021.661747. eCollection 2021.
ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of in children with short stature and to identify the underlying molecular mechanisms.
We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of . We subsequently examined the changes in protein expression and subcellular location in caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined.
We identified 12 mutations in in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments . The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2.
We expanded the mutational spectrum of in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.
ROR2是ROR家族的成员，作为Wnt5a的受体，对骨骼发育至关重要。本研究旨在调查身材矮小儿童中ROR2的突变谱，并确定潜在的分子机制。
我们通过对ROR2进行突变筛查，回顾性分析了426例身材矮小患者的临床表型和全外显子组测序（WES）数据。随后，我们检测了由这些突变引起的ROR2蛋白表达和亚细胞定位的变化。我们还检测了Wnt5a-ROR2途径下游信号分子的mRNA表达。
我们在21例患者的ROR2中鉴定出12个突变，包括10个错义突变、1个无义突变和1个移码突变。在所有错义变体中，通过实验分析了4个复发性错义变体[c.1675G>A（p.Gly559Ser）、c.2212C>T（p.Arg738Cys）、c.1930G>A（p.Asp644Asn）、c.2117G>A（p.Arg706Gln）]。c.1675G>A突变显著改变了ROR2蛋白的表达和细胞定位。c.1675G>A突变还导致c-Jun的表达显著降低。相比之下，其他错义变体对ROR2的生物学功能没有任何破坏作用。
我们扩展了身材矮小患者中ROR2的突变谱。功能实验可能揭示了一种新的分子机制，即ROR2中的c.1675G>A突变可能通过干扰蛋白的亚细胞定位和表达来影响下游Wnt5a-ROR2途径基因的表达。
