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

Elizabeth J Leslie; M Adela Mansilla; Leah C Biggs; Kristi Schuette; Steve Bullard; Margaret Cooper; Martine Dunnwald; Andrew C Lidral; Mary L Marazita; Terri H Beaty; Jeffrey C Murray

doi:10.1002/bdra.23076

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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

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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

Elizabeth J Leslie, M Adela Mansilla, Leah C Biggs, Kristi Schuette, Steve Bullard, Margaret Cooper, Martine Dunnwald, Andrew C Lidral, Mary L Marazita, Terri H Beaty, …

Birth defects research. A Clinical and molecular teratology, Vol.94(11), pp.934-942

11/2012

DOI: 10.1002/bdra.23076

PMCID: PMC3501616

PMID: 23008150

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https://www.ncbi.nlm.nih.gov/pmc/articles/3501616View

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Abstract

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. 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. 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. 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.

Signal Transduction

United States

Philippines

Mutation

Genome-Wide Association Study

Embryo, Mammalian

Exons

Humans

Interferon Regulatory Factors - genetics

Cleft Palate - genetics

Genetic Loci

Gene Regulatory Networks

Case-Control Studies

Cleft Lip - genetics

Animals

Chromosomes, Human, Pair 1

Cleft Lip - pathology

DNA Mutational Analysis

Gene Expression Regulation, Developmental

Cleft Palate - pathology

Female

Mice

GTPase-Activating Proteins - genetics

Details

Title: Subtitle: 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
Creators: Elizabeth J Leslie - Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, USA
M Adela Mansilla
Leah C Biggs
Kristi Schuette
Steve Bullard
Margaret Cooper
Martine Dunnwald
Andrew C Lidral
Mary L Marazita
Terri H Beaty
Jeffrey C Murray
Resource Type: Journal article
Publication Details: Birth defects research. A Clinical and molecular teratology, Vol.94(11), pp.934-942
DOI: 10.1002/bdra.23076
PMID: 23008150
PMCID: PMC3501616
NLM abbreviation: Birth Defects Res A Clin Mol Teratol
ISSN: 1542-0752
eISSN: 1542-0760
Publisher: Wiley; United States
Grant note: RC2 HL103010 / NHLBI NIH HHS T32 GM008629 / NIGMS NIH HHS DE020057 / NIDCR NIH HHS RC2 HL102924 / NHLBI NIH HHS UC2 HL102926 / NHLBI NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS RC2 HL102923 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS UC2 HL103010 / NHLBI NIH HHS UC2 HL102925 / NHLBI NIH HHS UC2 HL102924 / NHLBI NIH HHS R37 DE008559 / NIDCR NIH HHS DE08559 / NIDCR NIH HHS UC2 HL102923 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS U01 DE020057 / NIDCR NIH HHS
Language: English
Date published: 11/2012
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research; Iowa Institute of Human Genetics
Record Identifier: 9984025445402771

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