AUTHOR=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 TITLE=Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2021 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.661747 DOI=10.3389/fcell.2021.661747 ISSN=2296-634X ABSTRACT=Purpose

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 ROR2 in children with short stature and to identify the underlying molecular mechanisms.

Methods

We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a–ROR2 pathway was also examined.

Results

We identified 12 mutations in ROR2 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 in vitro. 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.

Conclusion

We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a–ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.