Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Fedik Rahimov; Mary L Marazita; Axel Visel; Margaret E Cooper; Michael J Hitchler; Michele Rubini; Frederick E Domann; Manika Govil; Kaare Christensen; Camille Bille; Mads Melbye; Astanand Jugessur; Rolv T Lie; Allen J Wilcox; David R Fitzpatrick; Eric D Green; Peter A Mossey; Julian Little; Regine P Steegers-Theunissen; Len A Pennacchio; Brian C Schutte; Jeffrey C Murray

doi:10.1038/ng.242

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Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Journal article

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Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip

Fedik Rahimov, Mary L Marazita, Axel Visel, Margaret E Cooper, Michael J Hitchler, Michele Rubini, Frederick E Domann, Manika Govil, Kaare Christensen, Camille Bille, …

Nature genetics, Vol.40(11), pp.1341-1347

10/05/2008

DOI: 10.1038/ng.242

PMCID: PMC2691688

PMID: 18836445

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Abstract

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2alpha and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

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Title: Subtitle: Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip
Creators: Fedik Rahimov
Mary L Marazita
Axel Visel
Margaret E Cooper
Michael J Hitchler
Michele Rubini
Frederick E Domann
Manika Govil
Kaare Christensen
Camille Bille
Mads Melbye
Astanand Jugessur
Rolv T Lie
Allen J Wilcox
David R Fitzpatrick
Eric D Green
Peter A Mossey
Julian Little
Regine P Steegers-Theunissen
Len A Pennacchio
Brian C Schutte
Jeffrey C Murray
Resource Type: Journal article
Publication Details: Nature genetics, Vol.40(11), pp.1341-1347
DOI: 10.1038/ng.242
PMID: 18836445
PMCID: PMC2691688
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Language: English
Date published: 10/05/2008
Academic Unit: Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pathology; Surgery; Pediatric Dentistry; Radiation Oncology; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025348802771

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