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 of CELSR1–3, 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 in CELSR1 (c.2609G>A p.P870L) was identified in both NTD and CHD patients. Both in vivo and in vitro assays revealed that CELSR1 P870L 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 in CELSR genes 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.
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IL-13 induced actin cytoskeleton rearrangement in human podocytes. Magnification, x60, scale bar, 20μm. For more information please see pp. 2317-2327. Image provided by Chan Chang Yien.
Research Article|
November 15 2016
Genetic analysis of rare coding mutations of CELSR1–3 in congenital heart and neural tube defects in Chinese people
Xiaojin Qiao;
Xiaojin Qiao
1
*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
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Yahui Liu;
Yahui Liu
1
*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
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Peiqiang Li;
Peiqiang Li
*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
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Zhongzhong Chen;
Zhongzhong Chen
*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
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Huili Li;
Huili Li
‡Capital Institute of Paediatrics, Beijing 100020, China
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Xueyan Yang;
Xueyan Yang
*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
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Richard H. Finnell;
Richard H. Finnell
†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.
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Zhangmin Yang;
Zhangmin Yang
¶Department of Biochemistry and Molecular Biology, College of life Sciences, Shaanxi Normal University, Xi'an 710062, China
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Ting Zhang;
Ting Zhang
‡Capital Institute of Paediatrics, Beijing 100020, China
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Bin Qiao;
Bin Qiao
∥Institute of Cardiovascular Disease, General Hospital of Jinan Military Region, Jinan 250022, China
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Yufang Zheng;
*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
**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
Correspondence: Hongyan Wang (email [email protected]) and Yufang Zheng (email [email protected]).
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Hongyan Wang
*State Key Laboratory of Genetic Engineering, MOE Key Laboratory of Contemporary Anthropology, 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
Correspondence: Hongyan Wang (email [email protected]) and Yufang Zheng (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 30 2016
Revision Received:
October 16 2016
Accepted:
October 17 2016
Accepted Manuscript online:
October 18 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (24): 2329–2340.
Article history
Received:
August 30 2016
Revision Received:
October 16 2016
Accepted:
October 17 2016
Accepted Manuscript online:
October 18 2016
Citation
Xiaojin Qiao, Yahui Liu, Peiqiang Li, Zhongzhong Chen, Huili Li, Xueyan Yang, Richard H. Finnell, Zhangmin Yang, Ting Zhang, Bin Qiao, Yufang Zheng, Hongyan Wang; Genetic analysis of rare coding mutations of CELSR1–3 in congenital heart and neural tube defects in Chinese people. Clin Sci (Lond) 1 December 2016; 130 (24): 2329–2340. doi: https://doi.org/10.1042/CS20160686
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