Abstract
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.
Highlights
To involve either a sterol 27-hydroxylase [7] or a sterol 24hydroxylase [8].The mechanism by which a defect in hepatic bile acid synthesis leads to thdeiverse symptoms observed in CTX is at present not known [4]; the pleiotropic nature of the disease does not appear tobe related to hypercholesterolemia as a majority of CTX patients have normal serum cholesterollevels [4]
By cholesterol in the nervous system is mardeeadily apparent Nylon filters(Biotrans)forblot hybridization experiments were in certain genetic diseases in which alterations in genes involved in sterol metabolism have profound effects on neural tissues
In patient CTX1, a mutation encoding a cysteine in place of an arginine was found (Fig. 3)
Summary
The sterol 27-hydroxylase gene in CTX subjects was first hydroxylase cDNA. The filters were exposed to Kndak XAR-5 x-ray film for 96 h in the presence of an intensifying screen. Examined in Southernblottingexperimentswith genomic The positions to which RNAs of known size DNA isolated from the fibroblasts of two unrelated affected to in the gel are shown on theleft of the figure. Reversion of the CTX2 mutationhy sitedirectedmutagenesisrestoredthecapacitytosynthesize a fully active enzyme (data not shown)
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