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

Choi, SJ and Marazita, ML and Hart, SP and Sulima, PP and Field, LL and McHenry, TG and Govil, M and Cooper, ME and Letra, A and Menezes, R and Narayanan, S and Mansilla, MA and Granjeiro, JM and Vieira, AR and Lidral, AC and Murray, JC and Hart, TC (2009) The PDGF-C regulatory region SNP rs28999109 decreases promoter transcriptional activity and is associated with CL/P. European Journal of Human Genetics, 17 (6). 774 - 784. ISSN 1018-4813

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Choi, SJ
Marazita, MLmarazita@pitt.eduMARAZITA
Hart, SP
Sulima, PP
Field, LL
McHenry, TG
Govil, M
Cooper, ME
Letra, A
Menezes, R
Narayanan, S
Mansilla, MA
Granjeiro, JM
Vieira, ARarv11@pitt.eduARV11
Lidral, AC
Murray, JC
Hart, TC
Date: 1 January 2009
Date Type: Publication
Journal or Publication Title: European Journal of Human Genetics
Volume: 17
Number: 6
Page Range: 774 - 784
DOI or Unique Handle: 10.1038/ejhg.2008.245
Schools and Programs: School of Dental Medicine > Dental Science
Refereed: Yes
ISSN: 1018-4813
MeSH Headings: Alleles; Case-Control Studies; Cleft Lip--genetics; Cleft Palate--genetics; Genetic Predisposition to Disease; Humans; Lymphokines--genetics; Platelet-Derived Growth Factor--genetics; Polymorphism, Single Nucleotide--genetics; Promoter Regions, Genetic--genetics; Transcription, Genetic--genetics
Other ID: NLM NIHMS94212, NLM PMC2788748
PubMed Central ID: PMC2788748
PubMed ID: 19092777
Date Deposited: 20 Sep 2012 20:12
Last Modified: 22 Jun 2021 14:56


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