Premium
Two novel mutations in the sterol 27‐hydroxylase gene causing cerebrotendinous xanthomatosis
Author(s) -
LamonFava S,
Schaefer EJ,
Garuti R,
Salen G,
Calandra S
Publication year - 2002
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1034/j.1399-0004.2002.610303.x
Subject(s) - cerebrotendinous xanthomatosis , cholestanol , compound heterozygosity , chenodeoxycholic acid , proband , biology , exon , endocrinology , microbiology and biotechnology , cyp27a1 , mutation , bile acid , medicine , genetics , biochemistry , gene , sterol , cholesterol
Cerebrotendinous xanthomatosis (CTX) is a rare recessive autosomal disease caused by mutations of the sterol 27‐hydroxylase gene. Clinically, CTX is characterized by tendon xanthomas, cataracts and progressive neurological deficits. Because of the disruption of the 27‐hydroxylase activity, CTX patients have elevated plasma levels of cholestanol, a by‐product of abnormal bile acid synthesis. The present authors describe a female patient with CTX. The proband in this study presented with elevated cholestanol levels, markedly reduced mitochondrial 27‐hydroxylase activity and altered bile acid composition. The 27‐hydroxylase gene was analysed for mutations by polymerase chain reaction amplification of the exons and the splice‐junction regions of the gene. The proband was found to be a compound heterozygote for two different mutations which have not been previously described: (1) a G → A transition at nucleotide 455 that is responsible for converting a glycine to a glutamic acid residue at amino acid position 112 (G112E); and (2) a five‐nucleotide deletion in exon 5 (from nucleotide 965 to 969) that is responsible for a shift in the reading frame and the insertion of a premature codon at position 296, and consequently, the synthesis of a truncated protein lacking the heme‐binding and andrenodoxin‐binding domains. Long‐term (18‐year) treatment of the proband with chenodeoxycholic acid (750 mg day −1 ) has been effective in preventing any progression of the disease.