Frontiers in Cell and Developmental Biology (Apr 2021)
Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature
- Baoheng Gui,
- Baoheng Gui,
- Baoheng Gui,
- Chenxi Yu,
- Chenxi Yu,
- Xiaoxin Li,
- Sen Zhao,
- Sen Zhao,
- Hengqiang Zhao,
- Hengqiang Zhao,
- Zihui Yan,
- Zihui Yan,
- Xi Cheng,
- Xi Cheng,
- Jiachen Lin,
- Jiachen Lin,
- Haiyang Zheng,
- Haiyang Zheng,
- Haiyang Zheng,
- Jiashen Shao,
- Jiashen Shao,
- Zhengye Zhao,
- Zhengye Zhao,
- Lina Zhao,
- Yuchen Niu,
- Zhi Zhao,
- Huizi Wang,
- Bobo Xie,
- Bobo Xie,
- Bobo Xie,
- Xianda Wei,
- Xianda Wei,
- Chunrong Gui,
- Chunrong Gui,
- Chuan Li,
- Chuan Li,
- Chuan Li,
- Shaoke Chen,
- Shaoke Chen,
- Shaoke Chen,
- Yi Wang,
- Yanning Song,
- Chunxiu Gong,
- Terry Jianguo Zhang,
- Terry Jianguo Zhang,
- Terry Jianguo Zhang,
- Terry Jianguo Zhang
Affiliations
- Baoheng Gui
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Baoheng Gui
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Baoheng Gui
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Chenxi Yu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Chenxi Yu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Xiaoxin Li
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Sen Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Sen Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Hengqiang Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Hengqiang Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zihui Yan
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Zihui Yan
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Xi Cheng
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Xi Cheng
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Jiachen Lin
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Jiachen Lin
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Haiyang Zheng
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Haiyang Zheng
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Haiyang Zheng
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Jiashen Shao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Jiashen Shao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zhengye Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Zhengye Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Lina Zhao
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Yuchen Niu
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Zhi Zhao
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Huizi Wang
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Bobo Xie
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Bobo Xie
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Bobo Xie
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Xianda Wei
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Xianda Wei
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Chunrong Gui
- Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Chunrong Gui
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Chuan Li
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Chuan Li
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Chuan Li
- Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Shaoke Chen
- The Guangxi Health Commission Key Laboratory of Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Shaoke Chen
- Department of Pediatric Endocrine and Metabolism, Maternal and Child Health Hospital of Guangxi, Nanning, China
- Shaoke Chen
- Department of Pediatrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
- Yi Wang
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
- Yanning Song
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
- Chunxiu Gong
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, National Center for Children’s Health, Capital Medical University, Beijing, China
- Terry Jianguo Zhang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Terry Jianguo Zhang
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Terry Jianguo Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Terry Jianguo Zhang
- 0Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
- DOI
- https://doi.org/10.3389/fcell.2021.661747
- Journal volume & issue
-
Vol. 9
Abstract
PurposeROR2, 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.MethodsWe 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.ResultsWe 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.ConclusionWe 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.
Keywords
