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. —Lee, M-H., S. Hazard, J. D. Carpten, S. Yi, J. Cohen, G.T. Gerhardt, G. Salen, and S. B. Patel. Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees.
Highlights
Medical University of South Carolina, Charleston, SC 29403; Prostate-Cancer Investigation Group Laboratory of Cancer Genetics,** National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; University of Texas Southwestern Medical Center,†† Dallas, TX 75235; Oregon Health Sciences
Known point mutations were mapped onto the models and demonstrate that several missense mutations occurred in the two areas, the adrenodoxin- and heme-binding domains, predicted a priori to be critical to protein function
This rare, autosomal, recessively inherited condition is caused by mutations affecting a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, encoded by the CYP27 gene
Summary
On the basis of clinical finding of tendon and tuberous xanthomas and elevated serum cholesterol and cholestanol levels. A total of 12 parents, 19 affected individuals, and 25 unaffected siblings were genotyped. The family tree of one proband, DB, was not available, but DNA from the proband was available as a fibroblast cell line. Informed consent was obtained from all participants in accordance with institutional review board requirements
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