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

被引：3

作者：

Feng, Xin ^{[1
,2
,3
,4
]}

Ye, Yongyu ^{[5
]}

Zhang, Jianan ^{[1
,6
]}

Zhang, Yuanqiang ^{[7
]}

Zhao, Sen ^{[2
,8
]}

Mak, Judith C. W. ^{[9
]}

Otomo, Nao ^{[10
,11
]}

Zhao, Zhengye ^{[2
,8
]}

Niu, Yuchen ^{[8
]}

Yonezawa, Yoshiro ^{[10
,11
]}

Li, Guozhuang ^{[2
,8
]}

Lin, Mao ^{[13
]}

Li, Xiaoxin ^{[1
,8
,12
]}

Cheung, Prudence Wing Hang ^{[6
]}

Xu, Kexin ^{[2
,8
]}

Takeda, Kazuki ^{[11
]}

Wang, Shengru ^{[2
]}

Xie, Junjie ^{[1
,4
]}

Kotani, Toshiaki ^{[10
]}

Choi, Vanessa N. T. ^{[4
]}

Song, You-Qiang ^{[4
,14
]}

Yang, Yang ^{[2
,8
]}

Luk, Keith Dip Kei ^{[6
]}

Lee, Kin Shing ^{[15
]}

Li, Ziquan ^{[2
,8
]}

Li, Pik Shan ^{[15
]}

Leung, Connie Y. H. ^{[15
]}

Lin, Xiaochen ^{[1
,4
]}

Wang, Xiaolu ^{[1
,6
]}

Qiu, Guixing ^{[2
,8
]}

Watanabe, Kota ^{[10
]}

Wu, Zhihong ^{[12
]}

Posey, Jennifer E. ^{[16
]}

Ikegawa, Shiro ^{[11
]}

Lupski, James R. ^{[16
,17
,18
,19
]}

Cheung, Jason Pui Yin ^{[6
,20
]}

Zhang, Terry Jianguo ^{[2
,3
,8
]}

Gao, Bo ^{[1
,4
,20
,21
,22
]}

Wu, Nan ^{[2
,3
,8
]}

机构：

[1] Chinese Univ Hong Kong, Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China

[2] Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, State Key Lab Complex Severe & Rare Dis, Dept Orthoped Surg, Beijing 100730, Peoples R China

[3] Chinese Acad Med Sci, Key Lab Big Data Spinal Deform, Beijing 100730, Peoples R China

[4] Univ Hong Kong, Li Ka Shing Fac Med, Sch Biomed Sci, Hong Kong, Peoples R China

[5] Southern Med Univ, Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Dept Orthoped Surg, Guangzhou 510080, Peoples R China

[6] Univ Hong Kong, Sch Clin Med, Li Ka Shing Fac Med, Dept Orthopaed & Traumatol, Hong Kong, Peoples R China

[7] Shandong Univ, Qilu Hosp, Cheeloo Coll Med, Dept Orthopaed Surg, Jinan 250012, Peoples R China

[8] Beijing Key Lab Genet Res Skeletal Deform, Beijing 100730, Peoples R China

[9] Univ Hong Kong, Li Ka Shing Fac Med, Dept Pharmacol & Pharm, Hong Kong, Peoples R China

[10] Keio Univ, Sch Med, Dept Orthoped Surg, Tokyo 1608582, Japan

[11] RIKEN Ctr Integrat Med Sci, Lab Bone & Joint Dis, Tokyo 1088639, Japan

[12] Chinese Acad Med Sci & Peking Union Med Coll, State Key Lab Complex Severe & Rare Dis, Dept Med Res Ctr, Beijing 100730, Peoples R China

[13] Zhejiang Univ, Affiliated Hosp 1, Sch Med, Dept Orthoped Surg, Hangzhou 310003, Peoples R China

[14] Univ Hong Kong, Shenzhen Hosp, Dept Med, Shenzhen 518009, Peoples R China

[15] Univ Hong Kong, Ctr Comparat Med Res, Hong Kong, Peoples R China

[16] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[17] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[18] Texas Childrens Hosp, Houston, TX 77030 USA

[19] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[20] Univ Hong Kong, Shenzhen Hosp, Dept Orthopaed & Traumatol, Shenzhen 518009, Peoples R China

[21] Ctr Translat Stem Cell Biol, Hong Kong, Peoples R China

[22] Chinese Univ Hong Kong, Key Lab Regenerat Med, Minist Educ, Sch Biomed Sci,Fac Med, Hong Kong, Peoples R China

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2024年 / 121卷 / 18期

基金：

美国国家卫生研究院; 中国国家自然科学基金; 中国博士后科学基金;

关键词：

congenital vertebral malformation; congenital scoliosis; somite; VANGL1/2; planar cell polarity (PCP); NEURAL-TUBE DEFECTS; FACIAL BRANCHIOMOTOR NEURONS; SOMITE SEGMENTATION; ROBINOW SYNDROME; TBX6; CAUSES; MUTATIONS; MOUSE; PROTEIN; PHOSPHORYLATION; MICE;

D O I：

10.1073/pnas.2310283121

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页数：12

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