Genetic variants in COL2A1, COL11A2, and IRF6 contribute risk to nonsyndromic cleft palate

Nikopensius, Tiit; Jagomägi, Triin; Krjutškov, Kaarel; Tammekivi, Veronika; Saag, Mare; Prane, Inga; Piekuse, Linda; Akota, Ilze; Barkane, Biruta; Krūmiņa, Astrīda; Ambrozaitytė, Laima; Matulevičienė, Aušra; Kučinskienė, Zita Aušrelė; Lāce, Baiba; Kučinskas, Vaidutis; Metspalu, Andres

doi:10.1002/bdra.20700

Cited by 40 publications

(53 citation statements)

References 43 publications

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“…COL11A2 is one of three distinct genes that encode collagen XI, which is expressed in the developing jaw in rats [43]. Genetic variants in COL11A2 can cause syndromic and non-syndromic palatal defects [44, 45]. …”

Section: Discussionmentioning

confidence: 99%

Distinct DNA methylation profiles in subtypes of orofacial cleft

Sharp

Davies

et al. 2017

Clin Epigenet

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BackgroundEpigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles.MethodsIn whole-blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only (CLO) n = 50; cleft palate only (CPO) n = 50; cleft lip and palate (CLP) n = 50). We also compared methylation in the blood to methylation in the lip or palate tissue using genome-wide data from the same 150 children and conducted an EWAS of CLO compared to CLP in lip tissue.ResultsWe found four genomic regions in blood differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. Several regions mapped to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA), and over 250 associations were novel. Methylation in blood correlated with that in lip/palate at some regions. There were 14 regions differentially methylated in the lip tissue from children with CLO and CLP, with one region (near KIAA0415) showing up in both the blood and lip EWAS.ConclusionsOur finding of distinct methylation profiles in different orofacial cleft (OFC) subtypes represents a promising first step in exploring the potential role of epigenetic modifications in the aetiology of OFCs and/or as clinically useful biomarkers of OFC subtypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0362-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Distinct DNA methylation profiles in subtypes of orofacial cleft

Sharp

Davies

et al. 2017

Clin Epigenet

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“…Alternations in the synthesis and accumulation of extracellular matrix proteins, including type II, IX, XI collagens, and proteoglycan 10-12 impair palatogenesis, all of that are regulated by Sox9 1,7-9 . Indeed, mutations in or around SOX9 gene result in palatal malformations in human and a mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have showed that Sox9 induces L-Sox5 and Sox6 transcription, and these Sox proteins coordinately regulate the expression of cartilage-specific extracellular matrix genes, including Col2a1, Col11a2 and Aggrecan 1,7-9 . Genetic variants in these genes also cause palatal malformation 10-12 . These findings indicate that Sox9 transcriptional activity has a regulatory role in palatogenesis.…”

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confidence: 99%

Wwp2 is essential for palatogenesis mediated by the interaction between Sox9 and mediator subunit 25

et al. 2011

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Sox9 is a direct transcriptional activator of cartilage-specific extracellular matrix genes and has essential roles in chondrogenesis. Mutations in or around the SOX9 gene cause campomelic dysplasia or Pierre Robin Sequence. However, Sox9-dependent transcriptional control in chondrogenesis remains largely unknown. Here we identify Wwp2 as a direct target of Sox9. Wwp2 interacts physically with Sox9 and is associated with Sox9 transcriptional activity via its nuclear translocation. A yeast two-hybrid screen using a cDNA library reveals that Wwp2 interacts with Med25, a component of the Mediator complex. The positive regulation of Sox9 transcriptional activity by Wwp2 is mediated by the binding between Sox9 and Med25. In zebrafish, morpholino-mediated knockdown of either wwp2 or med25 induces palatal malformation, which is comparable to that in sox9 mutants. These results provide evidence that the regulatory interaction between Sox9, Wwp2 and Med25 defines the Sox9 transcriptional mechanisms of chondrogenesis in the forming palate.

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“…Summing up all of the Zfps in the candidate region, their human homologs are located on 7q11, 11p15, 19p12-13, and 19q13. Among these regions, 19p12-13 has been associated with CLP in a genome-wide linkage study (Vieira et al, 2008) and 19q13 in other studies (Warrington et al, 2006;Nikopensius et al, 2010). The Nlrp genes are also a large family, and the closest human homolog to Nlrp4f appears to be NLRP4, also located on 19q13 (Hamatani et al, 2004).…”

Section: Discussionmentioning

confidence: 93%