title: Rare missense variants in DVL1, one of the human counterparts of the Drosophila dishevelled gene, do not confer increased risk for neural tube defects.
abstract: BACKGROUND
  Neural tube defects (NTDs) are severe malformations that arise when the neural tube fails to close during embryogenesis. The planar cell polarity pathway is involved in neural tube closure and has been implicated in the pathogenesis of NTDs both in animal models and human cohorts. Dishevelled (Dvl/Dsh) is a multi-module protein and a key regulator of both the canonical Wnt and the PCP pathway. In mouse, all Dvl1(-/-) ; Dvl2(-/-) double mutants display craniorachischisis, a severe form of open NTDs. Recently, we have reported a possible role for rare variants of DVL2 as risk factors for NTDs.
  
  
  METHODS
  In view of these data, we hypothesized that DVL1 mutations might increase the risk for NTDs in some cases. Resequencing of the DVL1 gene in a cohort of 473 NTDs patients and 150 ethnically matched controls was performed. Prediction of the downstream effects of the nonsynonymous variants was done using computational methods.
  
  
  RESULTS
  We identified six missense variants that were absent in our ethnically matched controls group, and four of them (p.Arg153Cys; p.Glu544Arg; p.Arg568Trp; p.Val644Phe) were predicted to have a functional effect on protein structure by one or more bioinformatic programs. However, there was no difference in the overall rate of deleterious variants between the patients and controls (four in patients and three in controls; p=0.36).
  
  
  CONCLUSIONS
  Our findings did not provide evidence for the implication of DVL1 in the pathogenesis of human NTDs.
authors.affiliation: UOC Neurochirurgia, Istituto Giannina Gaslini, Genova, Italia.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
authors.forename: Redouane
authors.initials: R
authors.lastname: Allache
authors.forename: Gianluca
authors.initials: G
authors.lastname: Piatelli
authors.forename: Armando
authors.initials: A
authors.lastname: Cama
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; D010750:Phosphoproteins; C000606588:dsh protein, Drosophila
keywords: convergent extension; dishevelled (DVL); neural tube defects (NTDs); planar cell polarity (PCP) pathway