Molecular Genetics of Familial Hyperlipidemias

结果如下：1)家族性高胆固醇血症（FH）的低密度脂蛋白受体（LDL-R）基因异常对来自210个家族的杂合型FH患者的LDL-R基因分析发现了4个新的突变体。(1) FH-Tonami-1：该LDL-R基因突变体显示约6kb的部分缺失，包括外显子15及其邻近的内含子。在正常培养的皮肤成纤维细胞中，大约120KD的LDL-R前体蛋白进入成熟的160KD，而在这种突变细胞中，较小的100KD前体蛋白从未进入成熟的形式，并在细胞中被破坏。(2) FH-Tonami-2：该突变体缺失约10kb，包括外显子2和3，并产生受体结合域的部分缺失。突变受体的活性约为正常的40%，因此，该突变体产生轻度型FH，该突变体的4例纯合子患者存活年龄分别为64岁、53岁、51岁和35岁。(3) FH-Kanazawa和FH-Okayama正在被证明是新的突变体LDL-R2)来自一个家庭的两个病人显示家族性缺陷载脂蛋白b - 100,显示一个点突变的外显子26日改变氨基酸3500 (Arg) Gln.3)胆甾醇酯转运蛋白(CETP)缺乏纯合子家族性hyper-HDL-emia已经证明是由CETP的不足,以及缺乏CETP基因已被证明是一个G的突变结14外显子和内含子的14。在日本发现10例纯合子和20例杂合子CETP缺乏症患者，发现CETP缺乏症可导致低ldl血症和高hdl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.