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

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, G4A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P ¼ 1 1011) 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.

Data di pubblicazione: 2008
Titolo: Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip
Autori: Fedik, Rahimov; Mary L., Marazita; Axel, Visel; Margaret E., Cooper; Michael J., Hitchler; Rubini, Michele; 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; NISC Comparative Sequencing, Program; Peter A., Mossey; Julian, Little; Regine P., Steegers Theunissen; Len A., Pennacchio; Brian C., Schutte; Jeffrey C., Murray
Rivista: NATURE GENETICS
Keywords: Cleft lip; Genetics; IRF6; AP-2A; SNP; Transcription factor
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, G4A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P ¼ 1 1011) 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.
Digital Object Identifier (DOI): 10.1038/ng.242
Handle: http://hdl.handle.net/11392/533499
Appare nelle tipologie:03.1 Articolo su rivista

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