Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Nikopensius, Tiit; Kempa, Inga; Ambrozaitytė, Laima; Jagomägi, Triin; Saag, Mare; Matulevičienė, Aušra; Utkus, Algirdas; Krjutškov, Kaarel; Tammekivi, Veronika; Piekuse, Linda; Akota, Ilze; Barkane, Biruta; Krūmiņa, Astrīda; Kloviņš, Jānis; Lāce, Baiba; Kučinskas, Vaidutis; Metspalu, Andres

doi:10.1002/bdra.20791

Cited by 43 publications

(54 citation statements)

References 37 publications

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“…A promoter variant in the TIMP2 (rs8179096) gene was also associated with NSCL/P (Letra et al, 2012a), corroborating previous association findings in Europeans (Nikopensius et al, 2011).…”

supporting

confidence: 88%

Functional Significance ofMMP3andTIMP2Polymorphisms in Cleft Lip/Palate

et al. 2014

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Evidence from biological and human studies strongly supports a role for MMP and TIMP genes as candidate genes for non-syndromic cleft lip with or without cleft palate (NSCL/P). We previously showed the association of promoter polymorphisms in MMP3 (rs3025058 and rs522616) and TIMP2 (rs8179096) with NSCL/P. In this study, we examined the functional significance of these polymorphisms. A specific DNA-protein complex for MMP3 rs522616 A was detected, and this allele by itself showed greater promoter activity than the G allele. However, the effect of rs522616 was ultimately regulated by the rs3025058 allele on the background. For TIMP2 rs8179096, the T allele showed a 2.5-fold increase in promoter activity when compared with allele C, whereas both C and T alleles were found to bind to nuclear factor kappa B. Our results provide new evidence that promoter polymorphisms in MMP3 and TIMP2 are functional and may affect gene transcription with possible effects on craniofacial development leading to NSCL/P.

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“…A promoter variant in the TIMP2 (rs8179096) gene was also associated with NSCL/P (Letra et al, 2012a), corroborating previous association findings in Europeans (Nikopensius et al, 2011).…”

supporting

confidence: 88%

Functional Significance ofMMP3andTIMP2Polymorphisms in Cleft Lip/Palate

et al. 2014

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“…Multiple other genome-wide linkage scans were performed for CL/P, each of which noted a number of positive signals; however, owing to limited sample size, few individual study results reached the standard levels of genome-wide significance [LOD scores ≥ 3.2 (73) for the typical 400-microsatellite-marker panel] until a consortium of research groups pooled their studies and achieved the first genome-wide significant results for CL/P in regions 1q32, 2p, 3q27-28, 9q21, 14q21-24, and 16q24 (86, 87). Follow-up fine mapping of these regions showed significant results for single-nucleotide polymorphisms (SNPs) in IRF6 , which had been previously associated in candidate gene studies (114) and was later also identified by genome-wide association studies (9, 13, 79), and in FOXE1 , which was later confirmed and strengthened with the results in other populations and from expression studies (78, 96, 107, 140). …”

Section: Evolution Of Human Genetic Studies Of Orofacial Cleftsmentioning

confidence: 55%

The Evolution of Human Genetic Studies of Cleft Lip and Cleft Palate

Marazita

2012

Annu. Rev. Genom. Hum. Genet.

191

167

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Orofacial clefts (OFCs)—primarily cleft lip and cleft palate—are among the most common birth defects in all populations worldwide, and have notable population, ethnicity, and gender differences in birth prevalence. Interest in these birth defects goes back centuries, as does formal scientific interest; scientists often used OFCs as examples or evidence during paradigm shifts in human genetics, and have also used virtually every new method of human genetic analysis to deepen our understanding of OFC. This review traces the evolution of human genetic investigations of OFC, highlights the specific insights gained about OFC through the years, and culminates in a review of recent key OFC genetic findings resulting from the powerful tools of the genomics era. Notably, OFC represents a major success for genome-wide approaches, and the field is poised for further breakthroughs in the near future.

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“…A search for potential (vertebrate) transcription factors binding to CpGs 83–85 revealed that CpG85 was a preferred target for HNF (or Forkhead box) proteins (Table 4), whereas CpG83 is a potential target for ISGF3, ELF-1, SP1 and NF-AT proteins. Foxc2 and Foxe1 have been identified as candidate genes for human syndromic and nonsyndromic palatal clefting, highlighting the importance of HNF proteins to palate development and the potentially critical role of CpG85 [64,65]. We therefore demonstrate, for the first time, that the developmental expression of Sox4 in the secondary palate is regulated via temporal changes in DNA methylation occurring at critical CpG residues located distal to the putative promoter.…”

Section: Discussionmentioning

confidence: 77%

Epigenetic Regulation of Sox4 during Palate Development

et al. 2013

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Aim Identification of genes that contribute to secondary palate development provide a better understanding of the etiology of palatal clefts. Gene-expression profiling of the murine palate from gestational days 12–14 (GD12–14), a critical period in palate development, identified Sox4 as a differentially expressed gene. In this study, we have examined if the differential expression of Sox4 in the palate is due to changes in DNA methylation. Materials & methods In situ hybridization analysis was used to localize the expression of Sox4 in the developing murine secondary palate. CpG methylation profiling of a 1.8-kb upstream region of Sox4 in the secondary palate from GD12–14 and transfection analysis in murine embryonic maxillary mesenchymal cells using Sox4 deletion, mutant and in vitro methylated plasmid constructs were used to identify critical CpG residues regulating Sox4 expression in the palate. Results Spatiotemporal analysis revealed that Sox4 is expressed in the medial edge epithelium and presumptive rugae-forming regions of the palate from GD12 to GD13. Following palatal shelf fusion on GD14, Sox4 was expressed exclusively in the epithelia of the palatal rugae, structures that serve as signaling centers for the anteroposterior extension of the palate, and that are thought to serve as neural stem cell niches. Methylation of a 1.8-kb region upstream of Sox4, containing the putative promoter, completely eliminated promoter activity. CpG methylation profiling of the 1.8-kb region identified a CpG-poor region (DMR4) that exhibited significant differential methylation during palate development, consistent with changes in Sox4 mRNA expression. Changes in the methylation of DMR4 were attributed primarily to CpGs 83 and 85. Conclusion Our studies indicate that Sox4 is an epigenetically regulated gene that likely integrates multiple signaling systems for mediating palatal fusion, palatal extension and/or the maintenance of the neural stem cell niche in the rugae.

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Variation in FGF1, FOXE1, and TIMP2genes is associated with nonsyndromic cleft lip with or without cleft palate

Cited by 43 publications

References 37 publications

Functional Significance ofMMP3andTIMP2Polymorphisms in Cleft Lip/Palate

Functional Significance ofMMP3andTIMP2Polymorphisms in Cleft Lip/Palate

The Evolution of Human Genetic Studies of Cleft Lip and Cleft Palate

Epigenetic Regulation of Sox4 during Palate Development

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