Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees

M. H. Lee, S. Hazard, J. D. Carpten, S. Yi, J. Cohen, G. T. Gerhardt, G. Salen, S. B. Patel

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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 CYP27locus, 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 CYP27gene]. 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.

Original languageEnglish (US)
Pages (from-to)159-169
Number of pages11
JournalJournal of Lipid Research
Volume42
Issue number2
StatePublished - 2001

Fingerprint

Cholestanetriol 26-Monooxygenase
Cerebrotendinous Xanthomatosis
Pedigree
Chromosomes
Exons
Adrenodoxin
Cholestanol
Mutation
Biosynthesis
Tendons
Enzyme activity
Bile Acids and Salts
Heme
Missense Mutation
Base Pairing
Genes
Plasmas
Juvenile Xanthogranuloma
Substrates
Genetic Heterogeneity

Keywords

  • Bile acids
  • Cholestanol
  • Cholesterol
  • Genetics

ASJC Scopus subject areas

  • Endocrinology

Cite this

Lee, M. H., Hazard, S., Carpten, J. D., Yi, S., Cohen, J., Gerhardt, G. T., ... Patel, S. B. (2001). Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. Journal of Lipid Research, 42(2), 159-169.

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. / Lee, M. H.; Hazard, S.; Carpten, J. D.; Yi, S.; Cohen, J.; Gerhardt, G. T.; Salen, G.; Patel, S. B.

In: Journal of Lipid Research, Vol. 42, No. 2, 2001, p. 159-169.

Research output: Contribution to journalArticle

Lee, MH, Hazard, S, Carpten, JD, Yi, S, Cohen, J, Gerhardt, GT, Salen, G & Patel, SB 2001, 'Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees', Journal of Lipid Research, vol. 42, no. 2, pp. 159-169.
Lee, M. H. ; Hazard, S. ; Carpten, J. D. ; Yi, S. ; Cohen, J. ; Gerhardt, G. T. ; Salen, G. ; Patel, S. B. / Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees. In: Journal of Lipid Research. 2001 ; Vol. 42, No. 2. pp. 159-169.
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AU - Carpten, J. D.

AU - Yi, S.

AU - Cohen, J.

AU - Gerhardt, G. T.

AU - Salen, G.

AU - Patel, S. B.

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