Sass C, Giroux L M, Ma Y, Roy M, Lavigne J, Lussier-Cacan S, Davignon J, Minnich A
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada.
Hum Genet. 1995 Jul;96(1):21-6. doi: 10.1007/BF00214181.
We describe a four-generation kindred with familial hypercholesterolemia (FH) in which two of the eight heterozygotes for a 5-kb deletion (exons 2 and 3) in the low density lipoprotein (LDL) receptor gene were found to have normal LDL-cholesterol levels. In our search for a gene responsible for the cholesterol-lowering effect in this family, we have studied variation in the genes encoding the LDL receptor, apolipoprotein (apo) B, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, apoAI-CIII-AIV, and lipoprotein lipase. The analysis showed that it was unlikely that variation in any of these genes was responsible for the cholesterol-lowering effect. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normo and hyperlipidemic subjects carrying the deletion. Analysis of the apo E isoforms revealed that most of the e2 allele carriers in this family, including the two normolipidemic 5-kb deletion carriers, were found to have LDL-cholesterol levels substantially lower than subjects with the other apo E isoforms. Thus, this kindred provides evidence for the existence of a gene or genes, including the apo e2 allele, with profound effects on LDL-cholesterol levels.
我们描述了一个患有家族性高胆固醇血症（FH）的四代家族，其中低密度脂蛋白（LDL）受体基因5 kb缺失（外显子2和3）的8名杂合子中有2名的LDL胆固醇水平正常。在寻找该家族中负责降低胆固醇作用的基因时，我们研究了编码LDL受体、载脂蛋白（apo）B、3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶、apoAI-CIII-AIV和脂蛋白脂肪酶的基因变异。分析表明，这些基因中的任何一个变异都不太可能是导致胆固醇降低作用的原因。通过活性和mRNA水平测量在体外评估的LDL受体表达，在携带该缺失的正常血脂和高脂血症受试者中相似。对apo E异构体的分析显示，该家族中的大多数e2等位基因携带者，包括两名血脂正常的5 kb缺失携带者，其LDL胆固醇水平明显低于携带其他apo E异构体的受试者。因此，这个家族为存在一个或多个对LDL胆固醇水平有深远影响的基因（包括apo e2等位基因）提供了证据。
