Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations

• 成果类型: Article
• 署名作者: Feng, Xin; Ye, Yongyu; Zhang, Jianan; Zhang, Yuanqiang; Zhao, Sen; Mak, Judith C. W.; Otomo, Nao; Zhao, Zhengye; Niu, Yuchen; Yonezawa, Yoshiro; Li, Guozhuang; Lin, Mao; Li, Xiaoxin; Cheung, Prudence Wing Hang; Xu, Kexin; Takeda, Kazuki; Wang, Shengru; Xie, Junjie; Kotani, Toshiaki; Choi, Vanessa N. T.; Song, You-Qiang; Yang, Yang; Luk, Keith Dip Kei; Lee, Kin Shing; Li, Ziquan; Li, Pik Shan; Leung, Connie Y. H.; Lin, Xiaochen; Wang, Xiaolu; Qiu, Guixing; Watanabe, Kota; Wu, Zhihong; Posey, Jennifer E.; Ikegawa, Shiro; Lupski, James R.; Cheung, Jason Pui Yin; Zhang, Terry Jianguo; Gao, Bo; Wu, Nan
• 署名单位: Chinese University of Hong Kong; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College Hospital; Peking Union Medical College; Chinese Academy of Medical Sciences - Peking Union Medical College; University of Hong Kong; Guangdong Academy of Medical Sciences & Guangdong General Hospital; Southern Medical University - China; University of Hong Kong; Shandong University; University of Hong Kong; Keio University; RIKEN; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Zhejiang University; University of Hong Kong; University of Hong Kong; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; University of Hong Kong; Chinese University of Hong Kong
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12600
• DOI: 10.1073/pnas.2310283121
• 发表日期: 2024-04-30
• 关键词: neural-tube defects; facial branchiomotor neurons; somite segmentation; robinow syndrome; tbx6 causes; mutations; mouse; protein; phosphorylation; mice

摘要

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ss - catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2 , many of which exhibited loss - of - function and dominant - negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock - in (p.R258H) mice exhibited vertebral malformations in a Vangl gene doseand environment - dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.