Bertolini S, Cassanelli S, Garuti R, Ghisellini M, Simone M L, Rolleri M, Masturzo P, Calandra S
Centro Prevenzione Arteriosclerosi, Università di Genova, Italy.
Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):408-18. doi: 10.1161/01.atv.19.2.408.
The aim of this study was the characterization of mutations of the LDL receptor gene in 39 Italian patients with homozygous familial hypercholesterolemia, who were examined during the period 1994 to 1996. The age of the patients ranged from 1 to 64 years; one third of them were older than 30. Plasma LDL cholesterol level ranged from 10.8 to 25.1 mmol/L. The residual LDL receptor activity, measured in cultured fibroblasts of 32 patients, varied from <2% to 30% of normal and was inversely correlated with the plasma LDL cholesterol level (r=-0.665; P<0.003). The most severe coronary atherosclerosis was observed in those patients with the lowest residual LDL receptor activity (</=5% of normal) and the highest plasma LDL cholesterol levels. Twenty-nine patients (23 of whom were unrelated) were found to be homozygotes at the LDL receptor locus. In this group we discovered 2 major rearrangements and 12 different point mutations (9 in the coding region and 3 in splice sites). Some mutations (D200G, C358R, V502M, G528D, and P664L) were found in 3 or more unrelated patients. Patients with the same mutation shared the same haplotype at the LDL receptor gene locus and came from the same geographic area. Ten patients (9 of whom were unrelated) were found to be compound heterozygotes. The mutations found in this group consisted of one large deletion and 12 point mutations (11 in the coding sequence and one in a splice site). In 3 compound heterozygotes we failed to identify the second mutant allele at the LDL receptor locus. These observations confirm the allelic heterogeneity underlying familial hypercholesterolemia in the Italian population and indicate that the variability of phenotypic expression of homozygous familial hypercholesterolemia is, to a large extent, related to the type of mutation of the LDL receptor gene.
本研究旨在对1994年至1996年期间接受检查的39名意大利纯合子家族性高胆固醇血症患者的低密度脂蛋白受体基因突变进行特征分析。患者年龄从1岁至64岁不等；其中三分之一年龄超过30岁。血浆低密度脂蛋白胆固醇水平在10.8至25.1 mmol/L之间。在32名患者的培养成纤维细胞中测得的残余低密度脂蛋白受体活性，从正常水平的<2%至30%不等，且与血浆低密度脂蛋白胆固醇水平呈负相关（r = -0.665；P < 0.003）。在残余低密度脂蛋白受体活性最低（≤正常水平的5%）且血浆低密度脂蛋白胆固醇水平最高的患者中观察到最严重的冠状动脉粥样硬化。29名患者（其中23名无亲缘关系）在低密度脂蛋白受体位点为纯合子。在该组中，我们发现了2种主要重排和12种不同的点突变（9种在编码区，3种在剪接位点）。一些突变（D200G、C358R、V502M、G528D和P664L）在3名或更多无亲缘关系的患者中被发现。具有相同突变的患者在低密度脂蛋白受体基因位点共享相同的单倍型，且来自相同的地理区域。10名患者（其中9名无亲缘关系）被发现为复合杂合子。该组中发现的突变包括1个大片段缺失和12种点突变（11种在编码序列中，1种在剪接位点）。在3名复合杂合子中，我们未能在低密度脂蛋白受体位点鉴定出第二个突变等位基因。这些观察结果证实了意大利人群中家族性高胆固醇血症背后的等位基因异质性，并表明纯合子家族性高胆固醇血症表型表达的变异性在很大程度上与低密度脂蛋白受体基因突变类型有关。
