Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects

Ciprian M. Bosoi, Valeria Capra, Redouane Allache, Vincent Quoc Huy Trinh, Patrizia De Marco, Elisa Merello, Pierre Drapeau, Alexander G. Bassuk, Zoha Kibar

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1371-1375
Number of pages5
JournalHuman Mutation
Volume32
Issue number12
DOIs
Publication statusPublished - Dec 2011

Fingerprint

Cell Polarity
Neural Tube Defects
Zebrafish
Mutation
Genes
Gastrulation
Neural Tube
Missense Mutation
Computational Biology
Causality
Animal Models
Phenotype

Keywords

  • Neural tube defects
  • NTD
  • PCP
  • Planar cell polarity
  • PRICKLE1
  • Rare mutations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. / Bosoi, Ciprian M.; Capra, Valeria; Allache, Redouane; Trinh, Vincent Quoc Huy; De Marco, Patrizia; Merello, Elisa; Drapeau, Pierre; Bassuk, Alexander G.; Kibar, Zoha.

In: Human Mutation, Vol. 32, No. 12, 12.2011, p. 1371-1375.

Research output: Contribution to journalArticle

Bosoi, Ciprian M. ; Capra, Valeria ; Allache, Redouane ; Trinh, Vincent Quoc Huy ; De Marco, Patrizia ; Merello, Elisa ; Drapeau, Pierre ; Bassuk, Alexander G. ; Kibar, Zoha. / Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects. In: Human Mutation. 2011 ; Vol. 32, No. 12. pp. 1371-1375.
@article{aa5cbe281ada4d828811458284367bb5,
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.",
keywords = "Neural tube defects, NTD, PCP, Planar cell polarity, PRICKLE1, Rare mutations",
author = "Bosoi, {Ciprian M.} and Valeria Capra and Redouane Allache and Trinh, {Vincent Quoc Huy} and {De Marco}, Patrizia and Elisa Merello and Pierre Drapeau and Bassuk, {Alexander G.} and Zoha Kibar",
year = "2011",
month = "12",
doi = "10.1002/humu.21589",
language = "English",
volume = "32",
pages = "1371--1375",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "John Wiley and Sons Inc.",
number = "12",

}

TY - JOUR

T1 - Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects

AU - Bosoi, Ciprian M.

AU - Capra, Valeria

AU - Allache, Redouane

AU - Trinh, Vincent Quoc Huy

AU - De Marco, Patrizia

AU - Merello, Elisa

AU - Drapeau, Pierre

AU - Bassuk, Alexander G.

AU - Kibar, Zoha

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Neural tube defects

KW - NTD

KW - PCP

KW - Planar cell polarity

KW - PRICKLE1

KW - Rare mutations

UR - http://www.scopus.com/inward/record.url?scp=81255171519&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=81255171519&partnerID=8YFLogxK

U2 - 10.1002/humu.21589

DO - 10.1002/humu.21589

M3 - Article

C2 - 21901791

AN - SCOPUS:81255171519

VL - 32

SP - 1371

EP - 1375

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 12

ER -