Autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes

常染色体显性高胆固醇血症是早发冠心病的重要危险因素。本研究的目的是阐明由载脂蛋白B基因突变引起的常染色体显性高胆固醇血症是否相对常见。对45个高胆固醇血症家系的LDL受体和载脂蛋白B基因进行了分析。在11个家系的LDL受体基因中检测到5种不同的部分缺失、2种不同的移码突变和1种复杂的核苷酸序列变化。8个LDL受体突变基因中有7个是新基因。此外，LDL受体基因RFLP单倍型分析也不否认另外19个家系的高胆固醇血症是由LDL受体基因突变引起的可能性。高胆固醇血症相对严重（血清胆固醇水平为100 ~ 300mg/dl），跟腱黄瘤在以上30个家系中的大多数中经常观察到。在其他15个家系中，高胆固醇血症和低密度脂蛋白受体基因RFLP没有被共分离，这表明高胆固醇血症是由于基因突变而不是低密度脂蛋白受体基因。高胆固醇血症是中度的（血清胆固醇水平，250-300mg/dl），跟腱黄瘤在这15个家系中很少观察到。对15个家系进行了高胆固醇血症与载脂蛋白B基因遗传标记的连锁分析。在15个家系中，有3个家系没有将高胆固醇血症和遗传标记共分离。对于其他12个家系，连锁分析没有提供信息。对于这12个家系，在先证者中分析了编码LDL受体结合域的载脂蛋白B基因区域的DNA序列。然而，到目前为止，载脂蛋白B基因DNA序列的异常尚未被检测到。这些数据表明，尽管大多数与跟腱黄瘤相关的相对严重的遗传性高胆固醇血症是由突变的LDL受体基因引起的，但许多遗传性中度高胆固醇血症并不是由突变的LDL受体基因引起的。载脂蛋白B基因突变引起的常染色体显性高胆固醇血症的患病率需要进一步的研究。少

Autosomal dominant hypercholesterolemia is an important risk factor for premature coronary heart disease. This study was done to clarify whether autosomal dominant hypercholesterolemia due to mutant apolipoprotein B genes is relatively common. The genes for LDL receptor and apolipoprotein B were analyzed in 45 pedigrees with hypercholesterolemia. Five different partial deletions, two different frameshift mutations and one complex nucleotide sequence changes were detected in the LDL receptor genes from 11 pedigrees. Seven of the 8 mutant LDL receptor mutant genes were novel ones. In addition, LDL receptor gene RFLP haplotype analysis did not deny the possibility that hypercholesterolemia of another 19 pedigrees is due to mutant LDL receptor genes. Hypercholesterolemia was relatively severe(serum cholesterol levels>300mg/dl)and Achilles tendon xanthomas were frequently observed in most of the above 30 pedigrees. In the other 15 pedigrees, hypercholesterolemia and LDL receptor gene RFLP h … More aplotypes were not co-segregated, suggesting that hypercholesterolemia is due to a mutation of the gene(s) other than the LDL receptor gene. Hypercholesterolemia was moderate (serum cholesterol levels, 250-300mg/dl) and Achilles tendon xanthomas were seldom observed in these 15 pedigrees. A linkage analysis between hypercholesterolemia and the genetic markers within the apolipoprotein B gene was done in the 15 pedigrees. In three of the 15 pedigrees, hypercholesterolemia and the genetic marker was not co-segregated. As to the other 12 pedigrees, the linkage analysis was not infomative. For these 12 pedigrees, DNA sequences in the region of the apolipoprotein B gene that codes for the LDL receptor-binding domain have been analyzed in the probands. Thus far, however, abnormalities in the DNA sequences of the apolipoprotein B gene have not been detected. These data suggest that many of hereditary moderate hypercholesterolemia are not due to the mutant LDL receptor genes, though most of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas are caused by the mutant LDL receptor genes. Further studies are needed to reveal the prevalence of autosomal dominant hypercholesterolemia due to the mutant apolipoprotein B genes. Less