Abstract
BackgroundBone morphogenetic protein 4 gene (BMP4) plays a key role during maxillofacial development, since orofacial clefts are observed in animals when this gene is conditionally inactivated. We recently reported the existence of association between nonsyndromic cleft lip/palate (NSCLP) and BMP4 polymorphisms by detecting transmission deviations for haplotypes that include a region containing a BMP4 promoter in case-parent trios. The aim of the present study was to search for possible causal mutations within BMP4 promoters (BMP4.1 and BMP4.2).MethodsWe analyzed the sequence of BMP4.1 and BMP4.2 in 167 Chilean NSCLP cases and 336 controls.ResultsWe detected three novel variants in BMP4.1 (c.-5514G > A, c.-5365C > T and c.-5049C > T) which could be considered as cleft risk factors due to their absence in controls. Additionally, rs2855530 G allele (BMP4.2) carriers showed an increased risk for NSCLP restricted to males (OR = 1.52; 95% C.I. = 1.07-2.15; p = 0.019). For this same SNP the dominant genotype model showed a higher frequency of G/G+G/C and a lower frequency of C/C in cases than controls in the total sample (p = 0.03) and in the male sample (p = 0.003). Bioinformatic prediction analysis showed that all the risk variants detected in this study could create new transcription factor binding motifs.ConclusionsThe sex-dependent association between rs2855530 and NSCLP could indirectly be related to the differential gene expression observed between sexes in animal models. We concluded that risk variants detected herein could potentially alter BMP4 promoter activity in NSCLP. Further functional and developmental studies are necessary to support this hypothesis.
Highlights
Bone morphogenetic protein 4 gene (BMP4) plays a key role during maxillofacial development, since orofacial clefts are observed in animals when this gene is conditionally inactivated
Four of them were found in BMP4.1: c.-5514G > A, c.-5365C > T, c.5109A > C and c.-5049C > T located at nucleotide 54424454, 54424305, 54424109 and 54423989 respectively
There is abundant evidence indicating that regulatory single-nucleotide polymorphism (SNP) have an impact in the phenotypic diversity and can affect disease susceptibility interacting with other variants located in their vicinity [31]
Summary
Bone morphogenetic protein 4 gene (BMP4) plays a key role during maxillofacial development, since orofacial clefts are observed in animals when this gene is conditionally inactivated. We recently reported the existence of association between nonsyndromic cleft lip/palate (NSCLP) and BMP4 polymorphisms by detecting transmission deviations for haplotypes that include a region containing a BMP4 promoter in case-parent trios. Nonsyndromic cleft lip with or without cleft palate (NSCLP [MIM 119530]) is one of the most common human craniofacial birth defects, with both genetic and environmental components involved in its etiology [1]. NSCLP presents a wide variety of primary and secondary medical complications in its rehabilitation. This fact plus medical costs and the emotional burden to patients and their families makes NSCLP a public health problem [3]. The identification of genetic risk factors in NSCLP has been the subject of intensive research in the last decades.
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