Abstract
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.
Highlights
Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease associated with accumulation of cholesterol and cholestanol in various tissues, especially tendons and neural tissues
- - - Supplementary key words cerebrotendinous xanthomatosis (CTX) Restriction fragment length polymorphism (RFLP) fibroblasts reverse transcription-polymerase chain reaction (RT-polymerase chain reaction (PCR)) cholestanol sociated with incomplete oxidation of the cholesterol side chain, leading to excretion of great amounts of C27-bile alcohols in bile, feces, and urine [5] as well as accumulation of cholestanol
Two different point mutations were identified in an African-American and a Canadian, respectively [10]. These two mutations were present in functional domains of the sterol 27-hydroxylase gene, the adrenodoxin and heme-ligand binding sites, Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by tendon xanthomas, dementia, cerebellar ataxia, premature atherosclerosis, and cataracts [1,2,3,4]
Summary
Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease associated with accumulation of cholesterol and cholestanol in various tissues, especially tendons and neural tissues. 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. 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.- Kim, K-S., s. Two different point mutations (in position 362, Arg to Cys, and in position 446, Arg to Cys) were identified in an African-American and a Canadian, respectively [10] These two mutations were present in functional domains of the sterol 27-hydroxylase gene, the adrenodoxin and heme-ligand binding sites, Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive sterol storage disease characterized by tendon xanthomas, dementia, cerebellar ataxia, premature atherosclerosis, and cataracts [1,2,3,4]. Considering the relatively high prevalence of CTX in Japan and the fact that there are more known cases here than in any other country [4, 12], it was considered important to elucidate the molecular basis for CTX inJapanese patients and to establish a method to diagnose the homozygous or heterozygous states
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