Choi Sun J, Marazita Mary L, Hart P Suzanne, Sulima Pawel P, Field L Leigh, McHenry Toby Goldstein, Govil Manika, Cooper Margaret E, Letra Ariadne, Menezes Renato, Narayanan Somnya, Mansilla Maria Adela, Granjeiro José M, Vieira Alexandre R, Lidral Andrew C, Murray Jeffrey C, Hart Thomas C
Human Craniofacial Genetic Section, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-1423, USA.
Eur J Hum Genet. 2009 Jun;17(6):774-84. doi: 10.1038/ejhg.2008.245. Epub 2008 Dec 17.
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.
人类连锁与关联研究表明，在4号染色体q31 - q32区域血小板衍生生长因子C（PDGF - C）基因座或其附近，存在一个与非综合征性唇裂伴或不伴腭裂（CL/P）相关的基因。小鼠Pdgfc(-/-)基因敲除实验表明，PDGF - C对腭发育至关重要。为评估PDGF - C在人类腭裂中的作用，我们对1048个CL/P家系以及来自多个地理区域的1000个病例对照样本进行了序列分析和单核苷酸多态性（SNP）基因分型。未发现编码区突变，但一个新的 - 986 C>T SNP（rs28999109）在中国家系的病例中与CL/P显著相关（P = 0.01），这为与4q31 - q32的连锁提供了证据。在美国、西班牙、印度、土耳其、中国和哥伦比亚的家系中，该SNP以及其他几个PDGF - C SNP也显示出显著或接近显著的关联，而在菲律宾和危地马拉的家系以及巴西的病例对照中未发现关联。 - 986T等位基因消除了六个重叠的潜在转录调控基序。PDGF - C启动子报告基因构建体的转染实验表明， - 986T等位基因与PDGF - C基因启动子活性显著降低（高达80%）相关。这种作用于易感遗传背景的功能多态性可能是人类CL/P病因的一个组成部分。
