Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.
Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis.
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发表时间：
1991-04
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通讯作者：
J. Cali;C. Hsieh;Chih-Lin Hsieh;U. Francke;U. Francke;D. Russell
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作者：
J. Cali;C. Hsieh;Chih-Lin Hsieh;U. Francke;U. Francke;D. Russell
胆固醇储存障碍性腱性黄瘤病（CTX）的特征是胆固醇和胆甾烷醇在多个组织中的异常沉积。沉积在中枢神经系统中导致神经功能障碍，其特征在于痴呆、脊髓轻瘫和小脑共济失调。沉积在其他组织中会引起肌腱黄瘤、过早的动脉粥样硬化和白内障。在两个不相关的CTX患者中，我们已经确定了编码胆固醇27-羟化酶（胆汁酸生物合成途径中的关键酶）的基因（CYP 27）中的不同点突变。将突变cDNA转染到培养的细胞中导致具有免疫反应性的甾醇27-羟化酶蛋白质的合成，酶活性大大降低。我们已经将CYP 27基因定位于人2号染色体的q33-qter间隔，和小鼠1号染色体，与CTX的常染色体隐性遗传模式一致。这些发现强调了甾醇在中枢神经系统中所起的重要作用，并表明其他甾醇代谢酶的突变可能导致具有神经系统表现的疾病。
The sterol storage disorder cerebrotendinous xanthomatosis (CTX) is characterized by abnormal deposition of cholesterol and cholestanol in multiple tissues. Deposition in the central nervous system leads to neurological dysfunction marked by dementia, spinal cord paresis, and cerebellar ataxia. Deposition in other tissues causes tendon xanthomas, premature atherosclerosis, and cataracts. In two unrelated patients with CTX, we have identified different point mutations in the gene (CYP27) encoding sterol 27-hydroxylase, a key enzyme in the bile acid biosynthesis pathway. Transfection of mutant cDNAs into cultured cells results in the synthesis of immunoreactive sterol 27-hydroxylase protein with greatly diminished enzyme activity. We have localized the CYP27 gene to the q33-qter interval of human chromosome 2, and to mouse chromosome 1, in agreement with the autosomal recessive inheritance pattern of CTX. These findings underscore the essential role played by sterols in the central nervous system and suggest that mutations in other sterol metabolizing enzymes may contribute to diseases with neurological manifestations.