Kim K S, Kubota S, Kuriyama M, Fujiyama J, Björkhem I, Eggertsen G, Seyama Y
Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo, Japan.
J Lipid Res. 1994 Jun;35(6):1031-9.
Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease associated with accumulation of cholesterol and cholestanol in various tissues, especially tendons and neural tissues. The biochemical defect that causes CTX is a deficiency of the mitochondrial sterol 27-hydroxylase which oxidizes the side chain of cholesterol in connection with formation of bile acids. Japan has a relatively high prevalence of CTX and more cases of the disease are found here than in any other country. In the present study two new different point mutations are described in the heme-ligand binding domain of the sterol 27-hydroxylase gene in three Japanese CTX patients and one CTX heterozygote. Two of the homozygotes as well as the heterozygote subject have a single base substitution of A for G at codon 441 [CGG (Arg) to CAG (Gln)]. Another homozygote has a transition of C to T at codon 441 [CGG (Arg) to TGG (Trp)]. These two different mutations result in two restriction fragment length polymorphisms (RFLPs) for the enzymes StuI or HpaII. We also assayed sterol 27-hydroxylase activity using skin fibroblasts derived from three CTX patients, one CTX heterozygote, and normal subjects. While two of the homozygous subjects have undetectable levels of the enzyme activity, one homozygous subject and one heterozygous subject have decreased levels of the enzyme activity, about 1.4% and 10% of normal, respectively. The results suggest that the newly identified point mutations in the sterol 27-hydroxylase gene could account for the sterol 27-hydroxylase deficiency in the Japanese CTX patients.
脑腱黄瘤病（CTX）是一种遗传性固醇贮积病，与胆固醇和胆甾烷醇在各种组织尤其是肌腱和神经组织中的蓄积有关。导致CTX的生化缺陷是线粒体固醇27 - 羟化酶缺乏，该酶在胆汁酸形成过程中氧化胆固醇的侧链。日本CTX的患病率相对较高，该国发现的该疾病病例比其他任何国家都多。在本研究中，描述了三名日本CTX患者和一名CTX杂合子的固醇27 - 羟化酶基因血红素配体结合域中的两种新的不同点突变。两名纯合子以及杂合子受试者在密码子441处有一个A对G的单碱基替换[CGG（精氨酸）变为CAG（谷氨酰胺）]。另一名纯合子在密码子441处有一个C到T的转换[CGG（精氨酸）变为TGG（色氨酸）]。这两种不同的突变导致了针对酶StuI或HpaII的两种限制性片段长度多态性（RFLP）。我们还使用来自三名CTX患者、一名CTX杂合子和正常受试者的皮肤成纤维细胞测定了固醇27 - 羟化酶活性。虽然两名纯合子受试者的酶活性水平检测不到，但一名纯合子受试者和一名杂合子受试者的酶活性水平降低，分别约为正常水平的1.4%和10%。结果表明，固醇27 - 羟化酶基因中新鉴定的点突变可能是日本CTX患者固醇27 - 羟化酶缺乏的原因。
