A 31 bp VNTR in the cystathionine β-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels
A 31 bp VNTR in the cystathionine β-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels
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DOI：
10.1038/sj.ejhg.5200679
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发表时间：
2001-08-01
影响因子：
5.2
通讯作者：
Blom, HJ
中科院分区：
文献类型：
--
作者：
Lievers, KJA;Kluijtmans, LAJ;Blom, HJ
高同型半胱氨酸代谢相关酶基因的分子缺陷可能导致轻度高同型半胱氨酸血症，这是心血管疾病（CVD）的一个独立和分级的危险因素。虽然胱硫醚β-合酶（CBS）缺陷的杂合性已被排除为血管疾病中轻度高同型半胱氨酸血症的主要遗传原因，但（非）编码DNA序列的突变可能导致CBS表达轻度降低，从而导致血浆同型半胱氨酸水平升高。我们在190例动脉闭塞性疾病患者和381例对照组中评估了跨越CBS基因外显子13-内含子13边界的31 bp VNTR与空腹、甲硫氨酸负荷后和甲硫氨酸负荷后血浆同型半胱氨酸水平升高之间的相关性。31 bp的VNTR由16、17、18、19或21个重复单元组成，并且随着重复单元数目的增加，血浆同型半胱氨酸浓度显示出显著增加，特别是在甲硫氨酸加载后。在26例血管疾病患者中，研究了培养的成纤维细胞中这31 bp VNTR与CBS酶活性之间的关系。CBS酶活性随着31 bp VNTR重复单元数的增加而降低。RT-PCR实验显示在外显子13-内含子13剪接位点存在选择性剪接。CBS基因中的31 bp VNTR与甲硫氨酸负荷后高同型半胱氨酸血症相关，这可能使个体易患心血管疾病的风险增加。
Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta -synthase (CBS) deficiency has been excluded as a major genetic cause of mild hype rhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16,17,18,19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.