Molecular Genetics of Familial Hyperlipidemias

结果如下：1)家族性高胆固醇血症(FH)患者低密度脂蛋白受体(LDL-R)基因异常对210个家系杂合子FH患者的分析发现了4个新的突变。(1)FH-Tonami-1：该低密度脂蛋白受体基因突变体包括外显子15及其邻近内含子，缺失约6kb。在正常培养的皮肤成纤维细胞中，约120KD的LDL-R前体蛋白进入成熟的160KD，而在该突变细胞中，100KD的较小前体从未进入成熟状态，并在细胞内被破坏。(2)FH-Tonami-2：该突变体包括外显子2和外显子3，缺失约10kb，并产生受体结合结构域的部分缺失。突变的受体活性约为正常的40%，因此，该突变产生了一种轻型性FH，该突变的四名纯合子患者存活到了，53，51，35岁。(3)FH-Kanazawa和FH-Okayama被证实为新的低密度脂蛋白-R2突变)2例家族性载脂蛋白B-100缺陷，表现为外显子26的一个点突变，将氨基酸3500(Arg)变为Gln。3)胆固醇酯转运蛋白(CETP)缺乏性纯合性家族性高密度脂蛋白血症已被证实是由CETP缺乏症引起的，CETP基因缺陷症已被证实是外显子14和内含子14交界处的G-A突变。CETP缺乏可导致低密度脂蛋白血症和高高密度脂蛋白血症。

Results are follows ;1) LDL-receptor (LDL-R) gene abnormalities in familial hypercholesterolemia (FH)LDL-R gene analysis of heterozygous FH patients from 210 families revealed four new mutants. (1) FH-Tonami-1 : This LDL-R gene mutant showed a partial deletion of about 6kb including exon 15 and its neighboring introns. In the normal cultured skin fibroblasts, about 120KD of LDL-R precursor protein proceeded into a mature 160KD, while in this mutant cells the smaller precursors of 100KD never proceeded into mature forms and were destroyed in the cells. (2) FH-Tonami-2 : This mutant shows a deletion of about 10kb including exons 2 and 3, and produces a partial deficiency of bind-binding domain of the receptor. The activity of the mutant receptor is about 40% of normal, and therefore, this mutant produces a mild type of FH, and the four homozygous patients of this mutant survive to reach the ages of 64, 53, 51, 35 years. (3) FH-Kanazawa and FH-Okayama are proved to be new mutants of LDL-R2) Two patients from a family showed the familial defective apolipoprotein B-100, showing one point mutation of exon 26, changing amino acid 3500 (Arg) into Gln.3) Cholesteryl ester transfer protein (CETP) deficiency Homozygous familial hyper-HDL-emia has proved to be produced by a deficiency of CETP, and the deficiency of the CETP gene has been proved to be a G to A mutation of the junction of exon 14 and intron 14. Ten homozygous and 20 heterozygous patients with CETP deficiency were discovered in Japan, and the deficiency of CETP has been found to produce a hypo-LDL-emia as well hyper-HDL-emia.