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

作者：Feng Xin, Yongyu Ye, Jianan Zhang, Yuanqiang Zhang, Sen Zhao, Jcw Mak, Nao Otomo, Zhengye Zhao, Yuchen Niu, Yoshiro Yonezawa, Guozhuang Li, Mao Lin, Xiaoxin Li, Prudence Wing Hang Cheung, Kexin Xu, Kazuki Takeda, Shengru Wang, Junjie Xie, Toshiaki Kotani, Vanessa N. T. Choi, You‐Qiang Song, Yang Yang, K.D.K. Luk, Kin Shing Lee, Ziquan Li, Pik Shan Li, Connie Y. H. Leung, Xiaochen Lin, Xiaolu Wang, Guixing Qiu, DISCO (Deciphering disorders Involving Scoliosis and COmorbidities) study group, Kota Watanabe, Zhihong Wu, Jennifer E. Posey, Shiro Ikegawa, James R. Lupski, Jason Pui Yin Cheung, Jianguo Zhang, Bo Gao, Nan Wu, Guixing Qiu, Nan Wu, Jianguo Zhang, Zhihong Wu, Shengru Wang, Sen Liu, Ziquan Li, Yang Yang, Z Y Zhao, Guilin Chen, Guozhuang Li, Yuanpeng Zhu, Jihao Cai, Di Liu, K F Xu, Jianle Yang, Aoran Maheshati, Qing Li, Jingyi Xie, Xiangjie Yin, Jie Wang, Zihua Li, Zhifa Zheng, Kun Fang, Xiangyu Nie, Xi Cheng, Wen Wen, Xinyu Yang, Yuanqiang Zhang, Lian Liu, Lianlei Wang, Na Chen, Jiachen Lin, Mao Lin, Lina Zhao, Fei Liu, Yuchen Niu, Qing Liu, Guangxi Gao, Shuai Cheng Li, Yueyan Bai, Sen Zhao, Yongyu Ye, Hengqiang Zhao, Zefu Chen, Jiaqi Liu, Zihui Yan, Chenxi Yu, Jiashen Shao, Nao Otomo, Yoshiro Yonezawa, Kazuki Takeda, Yoji Ogura, Noriaki Kawakami, Toshiaki Koatani, Teppei Suzuki, Koki Uno, Hideki Sudo, Satoshi Inami, Hiroshi Taneichi, Hideki Shigematsu, Kei Watanabe, Ryo Sugawara, Yuki Taniguchi, Shohei Minami, Masaya Nakamura, Morio Matsumoto, Shiro Ikegawa, Kota Watanabe · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2310283121 · 被引用次数：8 · 研究领域：Wnt/β-catenin signaling in development and cancer、Mechanisms of cancer metastasis、Hippo pathway signaling and YAP/TAZ

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 dose- and 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.