Lievers K J, Kluijtmans L A, Heil S G, Boers G H, Verhoef P, van Oppenraay-Emmerzaal D, den Heijer M, Trijbels F J, Blom H J
Department of Pediatrics, University Medical Center Nijmegen, The Netherlands.
Eur J Hum Genet. 2001 Aug;9(8):583-9. doi: 10.1038/sj.ejhg.5200679.
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 hyperhomocysteinaemia 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.
参与同型半胱氨酸代谢的酶编码基因中的分子缺陷可能是轻度高同型半胱氨酸血症的原因，轻度高同型半胱氨酸血症是心血管疾病（CVD）的一个独立且分级的风险因素。尽管已排除胱硫醚β-合酶（CBS）缺乏的杂合性是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序列中的突变可能导致CBS表达轻度下降，从而导致血浆同型半胱氨酸水平升高。我们评估了一个跨越CBS基因外显子13-内含子13边界的31bp可变数目串联重复序列（VNTR）与190例动脉闭塞性疾病患者及381例对照者的空腹、蛋氨酸负荷后及蛋氨酸负荷后血浆同型半胱氨酸水平升高之间的关联。该31bp VNTR由16、17、18、19或21个重复单元组成，并且随着重复元件数量的增加，血浆同型半胱氨酸浓度显著升高，尤其是在蛋氨酸负荷后。在26例血管疾病患者中，研究了该31bp VNTR与培养成纤维细胞中CBS酶活性之间的关系。CBS酶活性随着31bp VNTR重复单元数量的增加而降低。逆转录聚合酶链反应（RT-PCR）实验显示了外显子13-内含子13剪接连接位点存在可变剪接的证据。CBS基因中的31bp VNTR与蛋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。
