Cali J J, Hsieh C L, Francke U, Russell D W
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
J Biol Chem. 1991 Apr 25;266(12):7779-83.
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.
固醇贮积症脑腱黄瘤病（CTX）的特征是胆固醇和胆甾烷醇在多个组织中异常沉积。在中枢神经系统中的沉积会导致以痴呆、脊髓麻痹和小脑共济失调为特征的神经功能障碍。在其他组织中的沉积会导致肌腱黄瘤、早发性动脉粥样硬化和白内障。在两名不相关的CTX患者中，我们在编码固醇27-羟化酶的基因（CYP27）中鉴定出不同的点突变，固醇27-羟化酶是胆汁酸生物合成途径中的关键酶。将突变cDNA转染到培养细胞中会导致免疫反应性固醇27-羟化酶蛋白的合成，但酶活性大大降低。我们已将CYP27基因定位到人类染色体2的q33-qter区间以及小鼠染色体1上，这与CTX的常染色体隐性遗传模式一致。这些发现强调了固醇在中枢神经系统中所起的重要作用，并表明其他固醇代谢酶的突变可能导致具有神经表现的疾病。
