Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2001-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520316758 |
| _version_ | 1818386690894462976 |
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| author | Mi-Hye Lee Starr Hazard John D. Carpten Sonia Yi Jonathan Cohen Glenn T. Gerhardt Gerald Salen Shailendra B. Patel |
| author_facet | Mi-Hye Lee Starr Hazard John D. Carpten Sonia Yi Jonathan Cohen Glenn T. Gerhardt Gerald Salen Shailendra B. Patel |
| author_sort | Mi-Hye Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T03:58:04Z |
| format | Article |
| id | doaj.art-911427fd9bb846929e137dd98f195904 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:58:04Z |
| publishDate | 2001-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-911427fd9bb846929e137dd98f1959042022-12-21T23:18:02ZengElsevierJournal of Lipid Research0022-22752001-02-01422159169Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigreesMi-Hye Lee0Starr Hazard1John D. Carpten2Sonia Yi3Jonathan Cohen4Glenn T. Gerhardt5Gerald Salen6Shailendra B. Patel7Division of Endocrinology, Medical University of South Carolina, Charleston, SC 29403Biomolecular Computing Resource, Medical University of South Carolina, Charleston, SC 29403Prostate-Cancer Investigation Group Laboratory of Cancer Genetics, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29403University of Texas Southwestern Medical Center, Dallas, TX 75235Oregon Health Sciences University, Portland, OR 97201University of Medicine and Dentistry, New Jersey Medical School, Newark, and Veterans Affairs Medical Center, New Jersey Healthcare System, East Orange, NJ 07103Medical University of South Carolina Strom Thurmond Building, Room 541, 114 Doughty Street Charleston SC 29403; Division of Endocrinology, Medical University of South Carolina, Charleston, SC 29403Cerebrotendinous 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.http://www.sciencedirect.com/science/article/pii/S0022227520316758geneticscholesterolcholestanolbile acids |
| spellingShingle | Mi-Hye Lee Starr Hazard John D. Carpten Sonia Yi Jonathan Cohen Glenn T. Gerhardt Gerald Salen Shailendra B. Patel Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees Journal of Lipid Research genetics cholesterol cholestanol bile acids |
| title | Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees |
| title_full | Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees |
| title_fullStr | Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees |
| title_full_unstemmed | Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees |
| title_short | Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees |
| title_sort | fine mapping mutation analyses and structural mapping of cerebrotendinous xanthomatosis in u s pedigrees |
| topic | genetics cholesterol cholestanol bile acids |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520316758 |
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