Molecular Genetics of Familial Hyperlipidemias

结果如下：1）家族性高胆固醇血症（FH）患者的LDL受体（LDL-R）基因异常对210个FH杂合子家系的LDL-R基因进行分析，发现4个新的突变。(1)FH-Tonami-1：该LDL-R基因突变体包括外显子15及其邻近的内含子，缺失约6 kb。在正常培养的皮肤成纤维细胞中，约120 KD的LDL-R前体蛋白进入成熟的160 KD，而在该突变细胞中，较小的100 KD前体蛋白从未进入成熟形式，并在细胞中被破坏。(2)FH-Tonami-2：该突变体缺失了包括外显子2和3在内的约10 kb的片段，并导致受体结合区的部分缺失。突变受体的活性约为正常的40%，因此，该突变体产生轻度FH，并且该突变体的四个纯合子患者存活达到64、53、51、35岁。(3)FH-Kanazawa和FH-Okayama被证明是LDL-R的新突变体2）来自一个家族的两名患者表现出家族性载脂蛋白B-100缺陷，表现为外显子26的一个点突变，将氨基酸3500（Arg）改变为Gln。3）胆固醇酯转移蛋白（CETP）缺乏症已被证明是由CETP缺乏症引起的纯合子家族性高HDL血症，CETP基因的缺失已被证明是外显子14和内含子14连接处的G到A突变。在日本发现了10例CETP缺乏症纯合子和20例杂合子患者，发现CETP缺乏症可引起低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.