Edinburgh Research Explorer Disruption of an AP-2alpha binding site in an IRF6 enhancer is associated with cleft lip-猫眼课题宝

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2012

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F. Rahimov;M. Marazita;A. Visel;M. Cooper;M. Hitchler;Michele Rubini;F. Domann;M. Govil;Kaare Christensen;Camille Bille;M. Melbye;A. Jugessur;R. T. Lie;Allen J. Wilcox;David R. Fitzpatrick;Eric D. Green;Nisc Comparative;Sequencing Program;P. Mossey;Julian Little;R. Steegers-Theunissen;L. Pennacchio;Brian C. Schutte;Jeffrey C. Murray

此前，我们已经证明非综合征性唇裂伴或不伴腭裂（NSCL/P）1与干扰素调节因子6（IRF 6）2中的SNP密切相关。在这里，多物种序列比较鉴定了一种新的IRF 6增强子中的常见SNP（rs642961，G>A）。A等位基因在NSCL/P家族中显著过度传递（P=1×10 −11），特别是唇裂（CL）家族，而非腭裂家族。此外，A等位基因存在剂量效应，AG基因型CL的相对风险为1.68，AA基因型为2.40。EMSA和ChIP分析表明，风险等位基因破坏了转录因子AP-2 α的结合位点，小鼠中的表达分析将增强子活性定位于颅面和肢体结构。我们的研究结果将IRF 6和AP-2 α置于相同的发育途径中，并确定了一种调节元件中的高频变体，该调节元件对一种常见的复杂疾病有很大贡献。

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P)1, is strongly associated with SNPs in Interferon Regulatory Factor 6 (IRF6)2. Here, multispecies sequence comparisons identify a common SNP (rs642961, G>A) in a novel IRF6 enhancer. The A allele is significantly overtransmitted (P=1×10 −11 ) in families with NSCL/P, in particular with cleft lip (CL) but not cleft palate. Further, there is a dosage effect of the A allele, with the relative risk for CL 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-2 α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2 α in the same developmental pathway and identify a high frequency variant in a regulatory element contributing substantially to a common, complex disorder.

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

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