Yu Wenxin, Nohara Atsushi, Higashikata Toshinori, Lu Hong, Inazu Akihiro, Mabuchi Hiroshi
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8641, Japan.
Atherosclerosis. 2002 Dec;165(2):335-42. doi: 10.1016/s0021-9150(02)00249-6.
To determine the molecular basis of familial hypercholesterolemia (FH) in Japan, 200 unrelated patients with clinically diagnosed heterozygous FH were screened for mutations in coding and promoter region of the low density lipoprotein (LDL) receptor gene using denaturing gradient-gel electrophoresis (DGGE), DNA sequencing and Southern blotting analysis. About 37 different mutations in the LDL receptor gene were identified in 125 (62.5%) of the patients, 22 of these mutations have not been described before. The most common mutations were K790X (19.5%), P664L (6.0%), FH-Tonami-1 (6.0%), IVS15-3C>A (5.5%) and FH-Tonami-2 (4.5%), whereas the other mutations were rare. No apolipoprotein B (apoB) mutations responsible for familial ligand-defective apoB-100 (FDB) were identified. Polymorphisms of apolipoprotein E (apoE) and scavenger receptor class B type I (SR-BI) were observed to have minor effects on the lipid and lipoprotein profile. In 75 (32.5%) of the FH patients, LDL receptor gene mutations could not be identified. These patients had significantly lower total cholesterol (7.71+/-1.64 vs. 8.68+/-1.47 mmol/l, P<0.001) and LDL-cholesterol (6.02+/-1.51 vs. 6.87+/-1.47 mmol/l, P<0.001) in plasma, also a lower incidence of coronary heart disease (CHD) (22 vs. 29%, P=0.05) compared with patients with a LDL receptor gene mutation, suggesting that besides LDL receptor, defect of other genes involved in LDL metabolism may be a cause of FH with a milder phenotypic expression in Japanese population.
为确定日本家族性高胆固醇血症（FH）的分子基础，我们使用变性梯度凝胶电泳（DGGE）、DNA测序和Southern印迹分析，对200例临床诊断为杂合子FH的无亲缘关系患者的低密度脂蛋白（LDL）受体基因编码区和启动子区进行了突变筛查。在125例（62.5%）患者中鉴定出约37种不同的LDL受体基因突变，其中22种突变此前未见报道。最常见的突变是K790X（19.5%）、P664L（6.0%）、FH-富南-1（6.0%）、IVS15-3C>A（5.5%）和FH-富南-2（4.5%），而其他突变较为罕见。未发现导致家族性配体缺陷型载脂蛋白B-100（FDB）的载脂蛋白B（apoB）突变。观察到载脂蛋白E（apoE）和B类清道夫受体I型（SR-BI）的多态性对血脂和脂蛋白谱有轻微影响。在75例（32.5%）FH患者中，未鉴定出LDL受体基因突变。与LDL受体基因突变患者相比，这些患者血浆中的总胆固醇（7.71±1.64 vs. 8.68±1.47 mmol/L，P<0.001）和LDL胆固醇（6.02±1.51 vs. 6.87±1.47 mmol/L，P<（此处原文有误，根据前文推测应为P<0.001））显著降低，冠心病（CHD）发病率也较低（22% vs. 29%，P=0.05），这表明在日本人群中，除LDL受体外，其他参与LDL代谢的基因缺陷可能是FH表型较轻的一个原因。
