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. Pennacchio; Brian C. Schutte; Jeffrey C. Murray; NISC Comparative Sequencing Pr

doi:10.1038/ng.242

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 (Lead / Corresponding author), NISC Comparative Sequencing Pr

Research output: Contribution to journal › Article › peer-review

350 Citations (Scopus)

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 language	English
Pages (from-to)	1341-1347
Number of pages	7
Journal	Nature Genetics
Volume	40
Issue number	11
DOIs	https://doi.org/10.1038/ng.242
Publication status	Published - Nov 2008

Keywords

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

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Rahimov, F., Marazita, M. L., Visel, A., Cooper, M. E., Hitchler, M. J., Rubini, M., Domann, F. E., Govil, M., Christensen, K., Bille, C., Melbye, M., Jugessur, A., Lie, R. T., Wilcox, A. J., Fitzpatrick, D. R., Green, E. D., Mossey, P. A., Little, J., Steegers-Theunissen, R. P., ... NISC Comparative Sequencing Pr (2008). Disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip. Nature Genetics, 40(11), 1341-1347. https://doi.org/10.1038/ng.242

@article{377caae154ed497e8393ba6a4435e44e,

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

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.",

keywords = "OROFACIAL CLEFTS, ORAL CLEFTS, PALATE, GENE, POPULATION, SEQUENCES, POLYMORPHISMS, CONTRIBUTES, EXPRESSION, MUTATIONS",

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

year = "2008",

month = nov,

doi = "10.1038/ng.242",

language = "English",

volume = "40",

pages = "1341--1347",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "11",

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Rahimov, F, Marazita, ML, Visel, A, Cooper, ME, Hitchler, MJ, Rubini, M, Domann, FE, Govil, M, Christensen, K, Bille, C, Melbye, M, Jugessur, A, Lie, RT, Wilcox, AJ, Fitzpatrick, DR, Green, ED, Mossey, PA, Little, J, Steegers-Theunissen, RP, Pennacchio, LA, Schutte, BC, Murray, JC & NISC Comparative Sequencing Pr 2008, 'Disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip', Nature Genetics, vol. 40, no. 11, pp. 1341-1347. https://doi.org/10.1038/ng.242

TY - JOUR

T1 - Disruption of an AP-2 alpha binding site in an IRF6 enhancer is associated with cleft lip

AU - Rahimov, Fedik

AU - Marazita, Mary L.

AU - Visel, Axel

AU - Cooper, Margaret E.

AU - Hitchler, Michael J.

AU - Rubini, Michele

AU - Domann, Frederick E.

AU - Govil, Manika

AU - Christensen, Kaare

AU - Bille, Camille

AU - Melbye, Mads

AU - Jugessur, Astanand

AU - Lie, Rolv T.

AU - Wilcox, Allen J.

AU - Fitzpatrick, David R.

AU - Green, Eric D.

AU - Mossey, Peter A.

AU - Little, Julian

AU - Steegers-Theunissen, Regine P.

AU - Pennacchio, Len A.

AU - Schutte, Brian C.

AU - Murray, Jeffrey C.

AU - NISC Comparative Sequencing Pr

PY - 2008/11

Y1 - 2008/11

N2 - 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.

AB - 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.

KW - OROFACIAL CLEFTS

KW - ORAL CLEFTS

KW - PALATE

KW - GENE

KW - POPULATION

KW - SEQUENCES

KW - POLYMORPHISMS

KW - CONTRIBUTES

KW - EXPRESSION

KW - MUTATIONS

UR - http://www.scopus.com/inward/record.url?scp=55049105999&partnerID=8YFLogxK

U2 - 10.1038/ng.242

DO - 10.1038/ng.242

M3 - Article

SN - 1061-4036

VL - 40

SP - 1341

EP - 1347

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

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

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Keywords

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