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

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...

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Published in:Birth defects research. A Clinical and molecular teratology 2012-11, Vol.94 (11), p.934-942
Main Authors: Leslie, Elizabeth J., Mansilla, M. Adela, Biggs, Leah C., Schuette, Kristi, Bullard, Steve, Cooper, Margaret, Dunnwald, Martine, Lidral, Andrew C., Marazita, Mary L., Beaty, Terri H., Murray, Jeffrey C.
Format: Article
Language:English
Subjects:
Animals
ARHGAP29
candidate gene
Case-Control Studies
Chromosomes, Human, Pair 1
Cleft Lip - genetics
Cleft Lip - pathology
cleft lip and palate
Cleft Palate - genetics
Cleft Palate - pathology
complex traits
DNA Mutational Analysis
Embryo, Mammalian
Exons
Female
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Genetic Loci
Genome-Wide Association Study
GTPase-Activating Proteins - genetics
Humans
Interferon Regulatory Factors - genetics
Mice
Mutation
Philippines
Rho signaling
Signal Transduction
United States
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Summary: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. CONCLUSION 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.
ISSN:1542-0752
1542-0760
DOI:10.1002/bdra.23076