title: Genetic analysis of a Japanese cerebrotendinous xanthomatosis family: identification of a novel mutation in the adrenodoxin binding region of the CYP 27 gene.
abstract: Cerebrotendinous xanthomatosis (CTX), an autosomal recessive lipid-storage hereditary disorder, is caused by mutations in the sterol 27-hydroxylase gene (CYP 27). A 24-year-old female Japanese CTX patient and her parents were studied for a CYP 27 mutation. Multiple xanthomas were the main complaint of the patient and plasma cholestanol level was markedly elevated. Sterol analysis of a xanthoma biopsy confirmed cholesterol and cholestanol deposition, and the cholestanol accounted for 8.1% of the total sterols. Sterol 27-hydroxylase activity in fibroblasts derived from the patient was undetectable, while the activities in fibroblasts from her mother and father were 54% and 41% of the normal level, respectively. Direct sequence analysis showed a missense mutation of A for G substitution in the CYP 27 gene at codon 362 (CGT 362Arg to CAT 362His) with a homozygous pattern in the patient, and a heterozygous pattern in the parents. The mutation, which eliminates a normal HgaI endonuclease site at position 1195 of the cDNA and is located at the adrenodoxin binding region of the gene, is most probably responsible for the decreased sterol 27-hydroxylase activity in this Japanese CTX family. The combined data strongly support that the primary enzymatic defect in CTX is the disruption of sterol 27-hydroxylase and that the disease is inherited in an autosomal recessive trait.
authors.affiliation: Department of Physiological Chemistry and Nutrition, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Kubota
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.forename: S
authors.initials: S
authors.lastname: Nozaki
authors.forename: S
authors.initials: S
authors.lastname: Yamashita
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: K
authors.initials: K
authors.lastname: Kameda-Takemura
authors.forename: M
authors.initials: M
authors.lastname: Menju
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuzawa
authors.forename: I
authors.initials: I
authors.lastname: Björkhem
authors.forename: G
authors.initials: G
authors.lastname: Eggertsen
authors.forename: Y
authors.initials: Y
authors.lastname: Seyama
mesh_terms: D000325:Adrenodoxin / Q000378:metabolism; D001665:Binding Sites; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005808:Genes, Recessive; D006801:Humans; D007564:Japan / Q000208:ethnology; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D013250:Steroid Hydroxylases / Q000235:genetics*; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics*
chemical_list: D000325:Adrenodoxin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase