2014
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Abstract: Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations observed in humans, with 1 occurrence in every 500-1,000 births. A 640-kb noncoding interval at 8q24 has been associated with increased risk of non-syndromic CL/P in humans, but the genes and pathways involved in this genetic susceptibility have remained elusive. Using a large series of rearrangements engineered over the syntenic mouse region, we show that this interval contains very remote cis-acting enhancers tha… Show more

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Cited by 108 publications
(97 citation statements)
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References 62 publications
(224 reference statements)
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“…The SNP rs987525 at 8q24. 21, which has recently been demonstrated to be located in the region near a remote MYC-regulated enhancer 28 , was not validated in either Beaty's Asian trios 10 or in our study; the derived allele is so rare in Asian populations that studies of it cannot achieve sufficient power. We screened 500-kb regions around the SNP in our imputation results; however, we did not find any SNPs with Po1.0 Â 10 À 5 ( Supplementary Fig.…”
Section: Discussioncontrasting
confidence: 40%
“…The SNP rs987525 at 8q24. 21, which has recently been demonstrated to be located in the region near a remote MYC-regulated enhancer 28 , was not validated in either Beaty's Asian trios 10 or in our study; the derived allele is so rare in Asian populations that studies of it cannot achieve sufficient power. We screened 500-kb regions around the SNP in our imputation results; however, we did not find any SNPs with Po1.0 Â 10 À 5 ( Supplementary Fig.…”
Section: Discussioncontrasting
confidence: 40%
“…Known genes mapped to the area near the 8q24 gene desert include MYC and GSDMC, encoding myc proto-oncogene protein, and melanoma-derived leucine zipper-containing extranuclear factor, respectively. A recent study of murine embryos found that the orthologous 280-kb region adjacent to human rs987525 harboured potential craniofacial enhancer elements, suggesting the presence of a regulatory effect 32 .…”
Section: Discussionmentioning
confidence: 99%
“…Our observations corroborate those made elsewhere (Beaty et al 2010;Murray et al 2012) suggesting that the varied ethnic association of the rs987525 allele largely depends on its MAF in various populations. Current evidence suggests that although the 8q24 window is a gene desert, it harbors very remote cis-acting craniofacial enhancer elements that regulate the expression of oncogenic MYC in the developing face; perturbation of this regulatory network leads to craniofacial dysmorphologies, including sporadic CL/P, in mice (Uslu et al 2014). The C677T (rs1801133) SNP of MTHFR but not A1298C (rs1801131) has largely been associated with reduced risk for NSCL/P in Asians (Zhao et al 2014;Martinelli et al 2015; (Sozen et al 2009) replicated the association.…”
Section: Discussionmentioning
confidence: 99%