title: Expression and mutation analyses implicate ARHGAP29 as the etiologic gene for the cleft lip with or without cleft palate locus identified by genome-wide association on chromosome 1p22.
abstract: BACKGROUND
  Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and environmental factors. Genome-wide association studies have successfully identified five novel loci associated with NSCL/P, including a locus on 1p22.1 near the ABCA4 gene. Because neither expression analysis nor mutation screening support a role for ABCA4 in NSCL/P, we investigated the adjacent gene ARHGAP29.
  
  
  METHODS
  Mutation screening for ARHGAP29 protein coding exons was conducted in 180 individuals with NSCL/P and controls from the United States and the Philippines. Nine exons with variants in ARHGAP29 were then screened in an independent set of 872 cases and 802 controls. Arhgap29 expression was evaluated using in situ hybridization in murine embryos.
  
  
  RESULTS
  Sequencing of ARHGAP29 revealed eight potentially deleterious variants in cases including a frameshift and a nonsense variant. Arhgap29 showed craniofacial expression and was reduced in a mouse deficient for Irf6, a gene previously shown to have a critical role in craniofacial development.
  
  
  CONCLUSIONS
  The combination of genome-wide association, rare coding sequence variants, craniofacial specific expression, and interactions with IRF6 support a role for ARHGAP29 in NSCL/P and as the etiologic gene at the 1p22 genome-wide association study locus for NSCL/P. This work suggests a novel pathway in which the IRF6 gene regulatory network interacts with the Rho pathway via ARHGAP29. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Leslie
authors.forename: M Adela
authors.initials: MA
authors.lastname: Mansilla
authors.forename: Leah C
authors.initials: LC
authors.lastname: Biggs
authors.forename: Kristi
authors.initials: K
authors.lastname: Schuette
authors.forename: Steve
authors.initials: S
authors.lastname: Bullard
authors.forename: Margaret
authors.initials: M
authors.lastname: Cooper
authors.forename: Martine
authors.initials: M
authors.lastname: Dunnwald
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lidral
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian; D005091:Exons; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010679:Philippines; D015398:Signal Transduction; D014481:United States
chemical_list: C500429:ARHGAP29 protein, human; D020690:GTPase-Activating Proteins; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors