title: Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis.
abstract: BACKGROUND
  Neural tube defects (NTDs), including anencephaly and spina bifida, have a complex etiology. Defects in the planar cell polarity (PCP) signaling pathway have been strongly associated with NTDs in animal models and human cohorts. In this genetic study, we examined the core PCP gene CELSR1 in NTDs and caudal agenesis cases to determine whether mutations at this gene predispose to these defects.
  
  
  METHODS
  We sequenced the coding region and the exon-intron junctions of CELSR1 in a cohort of 473 patients affected with various forms of open and closed NTDs (412) or caudal agenesis (61). Novel and rare variants (<1%) were genotyped in a cohort of 639 ethnically-matched individuals. The effect of novel missense mutations absent in controls and in public databases on protein function was predicted in silico.
  
  
  RESULTS
  We identified in our cohort one nonsense mutation in exon 1 of CELSR1 that truncates the majority of the protein in one patient with NTD and one in-frame 12 bp deletion that removes a putative PKC phosphorylation "SSR" motif in one caudal agenesis patient. We also detected a total of 13 novel missense variants in 12 patients (11 NTDs and 1 caudal agenesis) that were predicted to be pathogenic in silico.
  
  
  CONCLUSIONS
  We detected novel CELSR1 mutations predicted to be pathogenic in 2.9% of our NTD cohort and 3.3% of our caudal agenesis cohort. Our findings implicate CELSR1 as a risk factor for NTDs or caudal agenesis and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
authors.affiliation: Department of Obstetrics and Gynecology, CHU Sainte Justine Research Center and University of Montréal, Montréal, Canada.
authors.forename: Redouane
authors.initials: R
authors.lastname: Allache
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002170:Canada; D016764:Cell Polarity / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000208:ethnology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D013131:Spine / Q000002:abnormalities*
chemical_list: C454220:CELSR1 cadherin, human; D015820:Cadherins