Disruption of an AP-2 alpha 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. PennacchioBrian C. Schutte, Jeffrey C. Murray, NISC Comparative Sequencing Pr

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    Abstract

    Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P)(1) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6)(2). 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-2a and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2a in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

    Original languageEnglish
    Pages (from-to)1341-1347
    Number of pages7
    JournalNature Genetics
    Volume40
    Issue number11
    DOIs
    Publication statusPublished - Nov 2008

    Keywords

    • OROFACIAL CLEFTS
    • ORAL CLEFTS
    • PALATE
    • GENE
    • POPULATION
    • SEQUENCES
    • POLYMORPHISMS
    • CONTRIBUTES
    • EXPRESSION
    • MUTATIONS

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