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Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.
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.
Affiliation
  • Feng X; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Ye Y; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Zhang J; Key laboratory of big data for spinal deformities, Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Zhang Y; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Zhao S; Department of Orthopedic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China.
  • Mak JCW; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Otomo N; Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Zhao Z; Department of Orthopaedic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • Niu Y; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Yonezawa Y; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Li G; Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Lin M; Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Li X; Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
  • Cheung PWH; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Xu K; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Takeda K; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Wang S; Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Xie J; Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Kotani T; Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
  • Choi VNT; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Song YQ; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Yang Y; Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • Luk KDK; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Lee KS; Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Li Z; Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Li PS; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Leung CYH; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Lin X; Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
  • Wang X; Laboratory of Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan.
  • Qiu G; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Watanabe K; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Wu Z; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Posey JE; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Ikegawa S; Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518009, China.
  • Lupski JR; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
  • Cheung JPY; Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China.
  • Zhang TJ; Department of Orthopaedics and Traumatology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Gao B; Center for Comparative Medicine Research, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Wu N; Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, all at Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
Proc Natl Acad Sci U S A ; 121(18): e2310283121, 2024 Apr 30.
Article in En | MEDLINE | ID: mdl-38669183
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spine / Zebrafish / Carrier Proteins / Cell Polarity / Membrane Proteins Limits: Animals / Female / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Affiliation country: China Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Spine / Zebrafish / Carrier Proteins / Cell Polarity / Membrane Proteins Limits: Animals / Female / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Document type: Article Affiliation country: China Country of publication: United States