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

被引：331

作者：

Rahimov, Fedik ^{[1
]}

Marazita, Mary L. ^{[2
]}

Visel, Axel ^{[3
]}

Cooper, Margaret E. ^{[2
]}

Hitchler, Michael J. ^{[4
]}

Rubini, Michele ^{[5
]}

Domann, Frederick E. ^{[4
]}

Govil, Manika ^{[2
]}

Christensen, Kaare ^{[6
]}

Bille, Camille ^{[6
]}

Melbye, Mads ^{[7
]}

Jugessur, Astanand ^{[8
]}

Lie, Rolv T. ^{[8
]}

Wilcox, Allen J. ^{[9
]}

Fitzpatrick, David R. ^{[10
]}

Green, Eric D. ^{[11
,12
]}

Mossey, Peter A. ^{[13
]}

Little, Julian ^{[14
]}

Steegers-Theunissen, Regine P. ^{[15
]}

Pennacchio, Len A. ^{[3
]}

Schutte, Brian C. ^{[1
]}

Murray, Jeffrey C. ^{[1
]}

机构：

[1] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA

[2] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA 15219 USA

[3] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Genome Div, Berkeley, CA 94720 USA

[4] Univ Iowa, Dept Radiat Oncol, Iowa City, IA 52242 USA

[5] Univ Ferrara, Med Genet Unit, Dept Expt Diagnost Med, I-44100 Ferrara, Italy

[6] Univ So Denmark, Inst Publ Hlth, Ctr Prevent Congenital Malinformat, DK-5000 Odense C, Denmark

[7] Danish Epidemiol Sci Ctr, State Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark

[8] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Epidemiol & Med Stat, N-5018 Bergen, Norway

[9] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA

[10] Western Gen Hosp, Med Res Council Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland

[11] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA

[12] NHGRI, US Natl Inst Hlth Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA

[13] Univ Dundee, Dent Hosp & Sch, Dundee DD1 4HR, Scotland

[14] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON K1H 8M5, Canada

[15] Univ Med Ctr, NL-3015 GD Rotterdam, Netherlands

来源：

NATURE GENETICS | 2008年 / 40卷 / 11期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

D O I：

10.1038/ng.242

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：1341 / 1347

页数：7

共 31 条

[1] Oral clefts and life style factors - A case-cohort study based on prospective Danish data [J].