Analysis of genes causing autosomal dominant hypercholesterolemia

为了阐明常染色体显性遗传性高胆固醇血症的遗传原因，对遗传性高胆固醇血症家系进行了编码低密度脂蛋白受体和载脂蛋白B基因的家系分析。在所有17个有相对严重的高胆固醇血症(胆固醇水平300-450 mg/dl)与跟腱黄色瘤相关的先证者家庭中，相对严重。高胆固醇血症与低密度脂蛋白受体基因的部分缺失、异常Taqi条带或RFLP有关，这表明与跟腱黄色瘤相关的相对严重的高胆固醇血症中的大多数(如果不是全部)是由低密度脂蛋白受体基因缺陷引起的。另一方面，在学校调查后通过家庭研究选择的10个遗传性高胆固醇血症家庭中，似乎只有两个家庭似乎是典型的家族性高胆固醇血症。其余8个家系中观察到中度遗传性高胆固醇血症。在8个家系中，有2个家系的低密度脂蛋白受体基因RFLP与高胆固醇血症有关，另有2个家系观察到家族性混合性高脂蛋白血症的临床特征。在其他4个家系中，有3个家系未发现低密度脂蛋白受体基因RFLP与高胆固醇血症的连锁关系。在这些家族性载脂蛋白B-100缺陷家系中未检测到载脂蛋白B-100基因。这些数据表明，中度遗传性高胆固醇血症比典型的家族性高胆固醇血症更常见，许多中度遗传性高胆固醇血症可能是由与低密度脂蛋白受体基因不同的基因缺陷引起的。

To clarify genetic causes of autosomal dominant hypercholesterolemia, pedigree analysis of genes encoding LDL receptor and apolipoprotein B were performed in families with hereditary hypercholesterolemia. In all 17 families with probands having relatively severe hypercholesterolemia (cholesterol levels 300- 450 mg/dl) associated with Achilles tendon xanthomas, relatively severe . hypercholesterolemia was linked with a partial deletion, an abnormal TaqI band, or RFLP of the LDL receptor gene, indicating that most of, if not all, the relatively severe hypercholesterolemia associated with Achilles tendon xanthomas is caused by a defective LDL receptor gene. On the other hand, only two families seemed to be classic familial hypercholesterolemia in ten families with hereditary hypercholesterolemia which were selected by family studies following school surveys. Moderate hereditary hypercholesterolemia was observed in the remaining eight families. Among the eight families, the LDL receptor gene RFLP was linked with hypercholesterolemia in two families and clinical,features of familial combined hyperlipoproteinemia were observed in another two families. No linkage relationship was observed between LDL receptor gene RFLP and hypercholesterolemia in three of the other four families. The gene for familial defective apolipoprotein B-100 was not detected in these families. These data suggest that moderate hereditary hypercholesterolemia is more common than classic familial hypercholesterolemia and that many of moderate hereditary hypercholesterolemia may be caused by a defective gene at the loci distinct from the LDL receptor gene.