title: Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.
abstract: 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.
authors: Department of Obstetrics and Gynecology, CHU Sainte Justine Research Center and University of Montreal, Montreal, Canada.
authors: Ciprian M
authors: CM
authors: Bosoi
authors: Valeria
authors: V
authors: Capra
authors: Redouane
authors: R
authors: Allache
authors: Vincent Quoc-Huy
authors: VQ
authors: Trinh
authors: Patrizia
authors: P
authors: De Marco
authors: Elisa
authors: E
authors: Merello
authors: Pierre
authors: P
authors: Drapeau
authors: Alexander G
authors: AG
authors: Bassuk
authors: Zoha
authors: Z
authors: Kibar
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007558:Italy; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D009436:Neural Tube Defects / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States; D015027:Zebrafish / Q000235:genetics
chemical_list: D060588:LIM Domain Proteins; C515173:PRICKLE1 protein, human; D025521:Tumor Suppressor Proteins