title: Role of the planar cell polarity gene Protein tyrosine kinase 7 in neural tube defects in humans.
abstract: BACKGROUND
  Neural tube defects (NTDs) are among the most common congenital defects affecting approximately 1 in 1000 live births in North America. Their etiology is complex including environmental and genetic factors. Defects in the planar cell polarity (PCP) signaling pathway have been strongly associated with NTDs in animal models and human cohorts. Protein tyrosine kinase 7 (Ptk7) was shown to cause a very severe form of NTDs called craniorachischisis in a mouse model and genetically interacts with a core PCP member Vangl2 where double heterozygotes suffer from spina bifida. In this study, we examined the role of PTK7 in human NTDs to determine whether variants at this gene predispose to these defects.
  
  
  METHODS
  We sequenced the coding region and the exon-intron junctions of PTK7 in a cohort of 473 patients affected with various forms of open and closed NTDs. Novel and rare variants(<1%) were genotyped in a cohort of 473 individuals. Their pathogenic effect was predicted in silico and functionally in an overexpression assay in a well-established zebrafish model.
  
  
  RESULTS
  We identified in our cohort 6 rare variants, 3 of which were absent in public databases. One variant, p.Gly348Ser, acted as a hypermorph when overexpressed in the zebrafish model.
  
  
  CONCLUSIONS
  We detected potentially pathogenic PTK7 variants in 1.1% of our NTD cohort. Our findings implicate PTK7 as a risk factor for NTDs and provide additional evidence for a pathogenic role of PCP signaling in these malformations.
authors.affiliation: CHU Ste-Justine Research Center, Montréal, Québec, Canada.
authors.forename: Mingqin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: De Marco
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merello
authors.affiliation: Department of Neurosciences, University of Montréal, Montréal, Québec, Canada.|CHUM Research Center, Montréal, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Drapeau
authors.affiliation: Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Capra
authors.affiliation: CHU Ste-Justine Research Center, Montréal, Québec, Canada.|Department of Neurosciences, University of Montréal, Montréal, Québec, Canada.
authors.forename: Zoha
authors.initials: Z
authors.lastname: Kibar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D016764:Cell Polarity / Q000235:genetics*; D015331:Cohort Studies; D006801:Humans; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D015815:Cell Adhesion Molecules; C096905:PTK7 protein, human; D020794:Receptor Protein-Tyrosine Kinases
keywords: PTK7; neural tube defects; planar cell polarity pathway; sequencing analysis; zebrafish model