MOLECULAR-BASIS OF APOLIPOPROTEIN-(A) ISOFORM SIZE HETEROGENEITY AS REVEALED BY PULSED-FIELD GEL-ELECTROPHORESIS
MOLECULAR-BASIS OF APOLIPOPROTEIN-(A) ISOFORM SIZE HETEROGENEITY AS REVEALED BY PULSED-FIELD GEL-ELECTROPHORESIS
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DOI：
10.1172/jci115248
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发表时间：
1991-06-01
影响因子：
15.9
通讯作者：
HOBBS, HH
中科院分区：
文献类型：
--
作者：
LACKNER, C;BOERWINKLE, E;HOBBS, HH
脂蛋白(a) [Lp(a)]是一种富含胆固醇的脂蛋白，其特点是其糖蛋白载脂蛋白(a) [apo(a)]的含量。由于与纤溶酶原kringle 4同源的富含半胱氨酸的序列数量不同，载脂蛋白(a)的大小在个体之间存在差异。这种变异的遗传基础在基因组水平上尚不清楚。在这项研究中，我们使用脉冲场凝胶电泳和基因组印迹技术从载脂蛋白(a)基因中鉴定了一个高度多态性的限制性片段。该片段包含kringle 4编码序列的多个串联重复序列，根据kringle 4编码序列的数量，长度在48 ~ 190kb之间变化。在102个无亲缘关系的美国白种人中，共鉴定出19种不同的等位基因，其中94%的个体具有2种不同的等位基因，并且可以通过脉冲场凝胶电泳的大小来区分。大小不均匀的程度比先前基于蛋白质表观分子质量的分析所认识到的要大得多。载脂蛋白(a)基因的大小与载脂蛋白(a)蛋白的大小直接相关，与血浆中Lp(a)的浓度呈负相关。对载脂蛋白(a)基因进行家族分离分析；具有相同载脂蛋白(a)基因型的兄弟姐妹血浆Lp(a)水平相似。这些结果表明，在正常人群中，血浆Lp(a)水平在很大程度上是由载脂蛋白(a)位点的等位基因决定的。
Lipoprotein(a) [Lp(a)] is a cholesterol-rich lipoprotein that is distinguished by its content of a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) varies in size among individuals owing to different numbers of cysteine-rich sequences that are homologous to kringle 4 of plasminogen. The genetic basis for this variation is not understood at the genomic level. In this study we used pulsed-field gel electrophoresis and genomic blotting to identify a highly polymorphic restriction fragment from the apo(a) gene. The fragment contains multiple tandem repeats of a kringle 4-encoding sequence and varies in length from 48 to 190 kb depending on the number of kringle 4-encoding sequences. A total of 19 different alleles were identified among 102 unrelated Caucasian Americans. 94% of individuals studied had two different alleles which could be distinguished by size on pulsed-field gel electrophoresis. The degree of size heterogeneity was much greater than had been previously appreciated based on the analysis of the apparent molecular mass of the protein.The size of the apo(a) gene correlated directly with the size of the apo(a) protein, and inversely with the concentration of Lp(a) in plasma. Segregation analysis of the apo(a) gene was performed in families; siblings with identical apo(a) genotypes had similar plasma levels of Lp(a). These results suggest that in the normal population, the level of plasma Lp(a) is largely determined by alleles at the apo(a) locus.