Berger G M, Pegoraro R J, Patel S B, Naidu P, Rom L, Hidaka H, Marais A D, Jadhav A, Naoumova R P, Thompson G R
Department of Chemical Pathology, University of Natal Medical School, Durban, South Africa.
J Lipid Res. 1998 May;39(5):1046-54.
Phytosterolemia is an autosomal recessive disorder characterized by the excessive absorption, reduced excretion, and consequent high tissue and plasma levels of plant sterols, by the presence of tendon xanthomas, and by premature atherosclerosis. Low HMG-CoA reductase (HRase) activity and mass have been reported in liver and mononuclear leucocytes and low mRNA levels in liver from phytosterolemic subjects. These results led to the proposal that the primary defect in this condition involves the HRase gene locus. We examined this hypothesis in phytosterolemic subjects and heterozygous parents from four unrelated families. A variable number tandem repeat (VNTR) polymorphism of the HRase gene in the three informative families and a ScrFI restriction fragment length polymorphism (RFLP) within intron 2 of the gene in one of these families, segregated independently of the disease phenotype. Biological parentage was confirmed in the family in whom both polymorphisms failed to segregate with the disorder. These results conclusively exclude the HRase gene locus as the site of the primary defect in phytosterolemia. The study was extended by examining plasma levels of mevalonic acid and lathosterol, both markers of cholesterol biosynthesis, in response to cholestyramine, a bile acid sequestrant that is known to up-regulate HRase. Oral administration of cholestyramine resulted in a substantial (7.7-fold) increase in mevaIonic acid levels in two phytosterolemic subjects, compared with a 2.2-fold rise in their obligate heterozygote parents and a 2.3-fold increase in three healthy control subjects. The lathosterol/cholesterol (L/C) ratio showed a quantitatively similar response. Baseline levels of mevalonate and the L/C ratio were low in the phytosterolemic patients in conformity with reports of reduced cholesterol biosynthesis and HRase activity in this disorder. These functional data provide support for the concept that the primary defect in phytosterolemia does not affect a trans gene locus responsible for the constitutive expression or regulation of HMG-CoA reductase.
植物甾醇血症是一种常染色体隐性疾病，其特征为植物甾醇过度吸收、排泄减少，进而导致组织和血浆中植物甾醇水平升高，伴有肌腱黄色瘤，并易患早发性动脉粥样硬化。据报道，植物甾醇血症患者肝脏和单核白细胞中的HMG - CoA还原酶（HRase）活性和含量较低，肝脏中的mRNA水平也较低。这些结果提示，该病的主要缺陷可能涉及HRase基因位点。我们在来自四个无亲缘关系家庭的植物甾醇血症患者及其杂合子父母中检验了这一假说。在三个信息充分的家庭中检测了HRase基因的可变数目串联重复（VNTR）多态性，并在其中一个家庭中检测了该基因内含子2内的ScrFI限制性片段长度多态性（RFLP），结果发现这些多态性与疾病表型独立分离。在两个多态性均未与疾病分离的家庭中，确定了生物学亲子关系。这些结果明确排除了HRase基因位点是植物甾醇血症主要缺陷所在位点的可能性。通过检测胆固醇生物合成的两个标志物——甲羟戊酸和羊毛甾醇的血浆水平，对该研究进行了扩展。已知胆汁酸螯合剂考来烯胺可上调HRase，口服考来烯胺后，两名植物甾醇血症患者的甲羟戊酸水平大幅升高（7.7倍），相比之下，其必然杂合子父母升高了2.2倍，三名健康对照者升高了2.3倍。羊毛甾醇/胆固醇（L/C）比值显示出类似的定量反应。植物甾醇血症患者的甲羟戊酸基线水平和L/C比值较低，这与该疾病中胆固醇生物合成减少和HRase活性降低的报道一致。这些功能数据支持了以下概念：植物甾醇血症的主要缺陷并不影响负责HMG - CoA还原酶组成型表达或调节的反式基因位点。
