期刊
HUMAN MUTATION
卷 32, 期 12, 页码 1371-1375出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.21589
关键词
PRICKLE1; planar cell polarity; PCP; neural tube defects; NTD; rare mutations
资金
- Fonds de la Recherche en Sante du Quebec
- SickKids Foundation
- Canadian Institutes for Health Research [86520, NIH 1R01 NS064159-01A1]
- Gaslini Foundation
- Telethon-Italy [GGP08051]
The planar cell polarity (PCP) pathway controls the process of convergent extension (CE) during gastrulation and neural tube closure, and has been implicated in the pathogenesis of neural tube defects (NTDs) in animal models and human cohorts. In this study, we analyzed the role of one core PCP gene PRICKLE1 in these malformations. We screened this gene in 810 unrelated NTD patients and identified seven rare missense heterozygous mutations that were absent in all controls analyzed and predicted to be functionally deleterious using bioinformatics. Functional validation of five PRICKLE1 variants in a zebrafish model demonstrated that one variant, p.Arg682Cys, antagonized the CE phenotype induced by the wild-type zebrafish prickle1a (zpk1a) in a dominant fashion. Our study demonstrates that PRICKLE1 could act as a predisposing factor to human NTDs and further expands our knowledge of the role of PCP genes in the pathogenesis of these malformations. 32:13711375, 2011. (C) 2011 Wiley Periodicals, Inc.
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