title: Genetic analysis of rare coding mutations ofCELSR1-3in congenital heart and neural tube defects in Chinese people.
abstract: The planar cell polarity (PCP) pathway is critical for proper embryonic development of the neural tube and heart. Mutations in these genes have previously been implicated in the pathogenesis of neural tube defects (NTDs), but not in congenital heart defects (CHDs) in humans. We systematically identified the mutation patterns ofCELSR1-3, one family of the core PCP genes, in human cohorts composed of 352 individuals with NTDs, 412 with CHDs and matched controls. A total of 72 disease-specific, rare, novel, coding mutations were identified, of which 37 were identified in patients with CHDs and 36 in patients with NTDs. Most of these mutations differed between the two cohorts, because only one novel missense mutation inCELSR1(c.2609G>A p.P870L) was identified in both NTD and CHD patients. Bothin vivoandin vitroassays revealed thatCELSR1P870L is a gain-of-function mutation. It up-regulates not only the PCP pathway, but also canonical WNT signalling in cells, and also induces both NTDs and CHDs in zebrafish embryos. As almost equal numbers of mutations were identified in each cohort, our results provided the first evidence that mutations inCELSRgenes are as likely to be associated with CHDs as with NTDs, although the specific mutations differ between the two cohorts. Such differences in mutation panels suggested that CELSRs [cadherin, EGF (epidermal growth factor), LAG (laminin A G-type repeat), seven-pass receptors)] might be regulated differently during the development of these two organ systems.
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Peiqiang
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Zhongzhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Capital Institute of Paediatrics, Beijing 100020, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.|Dell Pediatric Research Institute, Department of Pediatrics, Dell Medical School at the University of Texas, Austin, U.S.A.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: Department of Biochemistry and Molecular Biology, College of life Sciences, Shaanxi Normal University, Xi'an 710062, China.
authors.forename: Zhangmin
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Capital Institute of Paediatrics, Beijing 100020, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qiao
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China wanghy@fudan.edu.cn zhengyf@fudan.edu.cn.|Collaborative Innovation Centre for Genetics & Development, School of Life Sciences, Fudan University, Shanghai 200438, China.|Key Lab of Reproduction Regulation of NPFPC in SIPPR, Institute of Reproduction & Development in Obstetrics & Gynaecology Hospital, Fudan University, Shanghai, 200433, China.|Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai 200433, China.
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai 200438, China wanghy@fudan.edu.cn zhengyf@fudan.edu.cn.|Key Lab of Reproduction Regulation of NPFPC in SIPPR, Institute of Reproduction & Development in Obstetrics & Gynaecology Hospital, Fudan University, Shanghai, 200433, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
keywords: CELSR1–3; PCP pathway; congenital heart defects (CHDs); neural tube defects (NTDs)