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The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P

2008; Springer Nature; Volume: 17; Issue: 6 Linguagem: Inglês

10.1038/ejhg.2008.245

1476-5438

Sun Jin Choi, Mary L. Marazita, P. Suzanne Hart, Paweł Sulima, L. Leigh Field, Toby McHenry, Manika Govil, Margaret E. Cooper, Ariadne Letra, Renato Menezes, Sowmya Narayanan, M. Adela Mansilla, José Mauro Granjeiro, Alexandre R. Vieira, Andrew C. Lidral, Jeffrey C. Murray, Thomas C. Hart,

dental development and anomalies

Human linkage and association studies suggest a gene(s) for nonsyndromic cleft lip with or without cleft palate (CL/P) on chromosome 4q31-q32 at or near the platelet-derived growth factor-C (PDGF-C) locus. The mouse Pdgfc(-/-) knockout shows that PDGF-C is essential for palatogenesis. To evaluate the role of PDGF-C in human clefting, we performed sequence analysis and SNP genotyping using 1048 multiplex CL/P families and 1000 case-control samples from multiple geographic origins. No coding region mutations were identified, but a novel -986 C>T SNP (rs28999109) was significantly associated with CL/P (P=0.01) in cases from Chinese families yielding evidence of linkage to 4q31-q32. Significant or near-significant association was also seen for this and several other PDGF-C SNPs in families from the United States, Spain, India, Turkey, China, and Colombia, whereas no association was seen in families from the Philippines, and Guatemala, and case-controls from Brazil. The -986T allele abolished six overlapping potential transcription regulatory motifs. Transfection assays of PDGF-C promoter reporter constructs show that the -986T allele is associated with a significant decrease (up to 80%) of PDGF-C gene promoter activity. This functional polymorphism acting on a susceptible genetic background may represent a component of human CL/P etiology.