title: Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.
abstract: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene (CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.
authors.affiliation: Division of Endocrinology, Medical University of South Carolina, Charleston 29403, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Hazard
authors.forename: J D
authors.initials: JD
authors.lastname: Carpten
authors.forename: S
authors.initials: S
authors.lastname: Yi
authors.forename: J
authors.initials: J
authors.lastname: Cohen
authors.forename: G T
authors.initials: GT
authors.lastname: Gerhardt
authors.forename: G
authors.initials: G
authors.lastname: Salen
authors.forename: S B
authors.initials: SB
authors.lastname: Patel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D053493:Cholestanetriol 26-Monooxygenase; D018244:Chromosomes, Artificial, Yeast; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics*; D017931:DNA Primers; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D015995:Prevalence; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D019294:Xanthomatosis, Cerebrotendinous / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*
chemical_list: D017931:DNA Primers; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase