1. ¹Human Craniofacial Genetic Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
2. ²Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
4. ⁴Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
5. ⁵Department of Pediatrics, University of Iowa, Iowa City, IA, USA
6. ⁶Department of Cell and Molecular Biology, Fluminense Federal University, Niterói, Rio de Janeiro, Brazil
7. ⁷Department of Orthodontics, University of Iowa, Iowa City, IA, USA

Correspondence: Dr TC Hart, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 10, Room 5N-102, 10 Center Drive, Bethesda, MD 20892-1423, USA. Tel: +1 301 402 0262; Fax: +1 301 480 2055; E-mail: thart@mail.nih.gov

Received 26 May 2006; Revised 21 October 2008; Accepted 20 November 2008; Published online 17 December 2008.

Abstract

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.