Promoter haplotype combinations of the platelet-derived growth factor α-receptor gene predispose to human neural tube defects
Promoter haplotype combinations of the platelet-derived growth factor α-receptor gene predispose to human neural tube defects
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DOI：
10.1038/84867
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发表时间：
2001-02-01
期刊：
影响因子：
30.8
通讯作者：
Van Zoelen, EJJ
中科院分区：
文献类型：
--
作者：
Joosten, PHLJ;Toepoel, M;Van Zoelen, EJJ
神经管缺陷（NTDs），包括无脑畸形和脊柱裂，是多因素疾病，在英国发病率为1 / 300(1)。小鼠模型表明，编码血小板衍生生长因子α受体（Pdgfra）的基因表达失调导致先天性NTDs（参考文献）。2-4)，而与NTDs相关的Pax-1突变形式会导致人类PDGFRA启动子的失调控激活（2,5）。越来越多的人认识到遗传多态性可能在NTDs的易感性中起重要作用（参考文献6）。在这里，我们鉴定了人类PDGFRA启动子中的五种不同的单倍型，其中最丰富的两种，称为H1和H2 α，在至少六个多态性位点上存在差异。在人骨细胞的瞬时转染试验中，五种单倍型在增强报告基因活性的能力上存在很大差异。在一组散发性脊柱裂患者中，转录活性低的单倍型，包括H1，代表性不足，而转录活性高的单倍型，包括H2 α，代表性过高。当对单倍型组合进行检测时，散发性患者组中完全没有HI纯合子，而在散发性和家族性脊柱裂患者组中，H1/H2 α杂合子都是过度代表的，但在不相关的对照组中却严重缺乏代表。我们的数据表明，自然发生的PDGFRA启动子单倍型的特定组合强烈影响NTD的发生。
Neural tube defects (NTDs), including anencephaly and spina bifida, are multifactorial diseases that occur with an incidence of 1 in 300 births in the United Kingdom(1). Mouse models have indicated that deregulated expression of the gene encoding the platelet-derived growth factor alpha -receptor (Pdgfra) causes congenital NTDs (refs. 2-4), whereas mutant forms of Pax-1 that have been associated with NTDs cause deregulated activation of the human PDGFRA promoter(2,5). There is an increasing awareness that genetic polymorphisms may have an important role in the susceptibility for NTDs (ref. 6). Here we identify five different haplotypes in the human PDGFRA promoter, of which the two most abundant ones, designated H1 and H2 alpha, differ in at least six polymorphic sites. In a transient transfection assay in human bone cells, the five haplotypes differ strongly in their ability to enhance reporter gene activity. In a group of patients with sporadic spina bifida, haplotypes with low transcriptional activity, including H1, were under-represented, whereas those with high transcriptional activity, including H2 alpha, were over-represented. When testing for haplotype combinations, HI homozygotes were fully absent from the group of sporadic patients, whereas H1/H2 alpha heterozygotes were over-represented in the groups of both sporadic and familial spina bifida patients, but strongly underrepresented in unrelated controls. Our data indicate that specific combinations of naturally occurring PDGFRA promoter haplotypes strongly affect NTD genesis.