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

Rahimov, Fedik; Marazita, Mary L.; Visel, Axel; Cooper, Margaret E.; Hitchler, Michael J.; Rubini, Michele; Domann, Frederick E.; Govil, Manika; Christensen, Kaare; Bille, Camille; Melbye, Mads; Jugessur, Astanand; Lie, Rolv Terje; Wilcox, Allen J.; FitzPatrick, David R.; Green, Eric D.; Mossey, Peter; Little, Julian; Steegers‐Theunissen, R.P.M.; Pennacchio, Len A.; Schutte, Brian C.; Murray, Jeffrey C.

doi:10.1038/ng.242

Cited by 407 publications

(527 citation statements)

References 30 publications

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“…IRF6 gene expression has been shown previously to be regulated by the binding of the p63 transcription factor to an enhancer element located 9.7 kb upstream of the IRF6 transcription start site (55,56). However, IRF6-binding sites in the IRF6 gene have been identified, leading to the suggestion that IRF6 can also mediate its own expression (8).…”

Section: Discussionmentioning

confidence: 97%

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

Kwa

Huynh

et al. 2014

Journal of Biological Chemistry

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Background: RIPK4 and IRF6 are important for epidermal development. However, whether they function together to regulate keratinocyte differentiation has not been addressed. Results: RIPK4 directly activates IRF6, resulting in expression of the transcriptional regulators GRHL3 and OVOL1. Conclusion: RIPK4 and IRF6 promote keratinocyte differentiation by functioning as a signaling axis. Significance: This study reveals how mutations in RIPK4 may cause epidermal disorders.

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Section: Discussionmentioning

confidence: 97%

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

Kwa

Huynh

et al. 2014

Journal of Biological Chemistry

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“…31 AP-2a is known to be essential for craniofacial development and cranial closure 32 and has been implemented in NSCL/P. 33 Similarly in the analysis of NSCPO, a suggestive bias for maternal over-transmission was observed for rs6539608 located on chromosome 12q21. No genes or transcripts map to this region, making an interpretation of functional relevance difficult.…”

Section: Discussionmentioning

confidence: 97%

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

et al. 2013

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Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genomewide single-nucleotide polymorphism (SNP) data from B2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of B1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (Po5 Â 10 À8 ). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P ¼ 0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P ¼ 1.5 Â 10 À7 , paternal-specific P ¼ 0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

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“…7 ). Subsequent analyses identified a causative variant rs642961 in the IRF6 promoter region which disrupts the binding site of the transcription factor AP-2a involved in craniofacial development 8 . In this report, we found that rs642961 was associated with nsCL/P risk in all of the models of inheritance tested, with a 1.6 to almost a threefold increase in risk.…”

Section: Discussionmentioning

confidence: 99%

“…A variety of genetic approaches have been used to identify genes and pathways underlying nsCL/P. Before 2009, only one gene (interferon regulatory factor 6, IRF6) had been identified with a sufficient degree of consistency across studies, thus being considered a true nsCL/P-associated gene [7][8][9] . Association of nsCL/P with single nucleotide polymorphism (SNP) rs642961 in the IRF6 gene located at chromosomal region 1q32 was confirmed in candidate gene and genome-wide association studies (GWAS) of European-derived populations [10][11] .…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

Salagovic¹,

Klimčáková²,

Zabavnikova³

et al. 2017

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is the most common orofacial birth defect with an aetiology involving both genetic and environmental factors. Genome-wide association studies (GWAS) have identified several genomic susceptibility regions for nsCL/P. In the present study, the three well established single nucleotide polymorphisms (SNPs) identified by GWAS (rs987525 at 8q24, rs7078160 at 10q25, and rs227731 at 17q22 loci) and one SNP identified by candidate gene study (rs642961 in IRF6 gene at 1q32 locus) were analysed for an association with nsCL/P in Slovak population. Methods. Nucleotide variants were genotyped in 165 nsCL/P patients and 326 unaffected controls. All variants of interest were genotyped using high-resolution melting analysis after real-time PCR. Results. We found significant differences between patient and control groups with respect to the allele and genotype frequencies for the SNPs at the 1q32, 8q24, and 17q22 loci. SNP at the 10q25 locus showed a trend toward association with nsCL/P risk. Conclusions.The results suggest that SNPs at the 1q32, 8q24 and 17q22 loci may contribute to the nsCL/P risk in Slovak population.

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

Cited by 407 publications

References 30 publications

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

Receptor-interacting Protein Kinase 4 and Interferon Regulatory Factor 6 Function as a Signaling Axis to Regulate Keratinocyte Differentiation

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

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