The DOI matches its Crossref record; 85 of the 85 references it cites were found in a registry or an index.
Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.
Open accessAbstract
We describe a metabolic defect in bile acid synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.
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“whereas Cyp7b1 KO (sgCyp7b1) selectively reduced the presence of TCDCA (22)”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [22]
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Citations
Cites
Russell, D. W., & Setchell, K. D. R. (1992) · Biochemistry · doi:10.1021/bi00135a001 · Cited by 819
Self-citationHandbook of derivatives for chromatography
Blau, K., & Halket, J. M. (1978) · Andalas University Repository (Andalas University) · Cited by 795
Structure and function of cytochromes P450: a comparative analysis of three crystal structures
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Self-citationMyant, N. B., & Mitropoulos, K. A. (1977) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)41693-1 · Cited by 521
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Self-citationDisruption of Cholesterol 7α-Hydroxylase Gene in Mice
Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden, H. J., Zerwekh, J. E., Björkhem, I., Herz, J., & Russell, D. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.30.18024 · Cited by 270
Self-citationByler disease. Fatal familial intrahepatic cholestasis in an Amish kindred.
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Self-citation
Research works printed but not linked: 2
- [25]25. Setchell, K.D.R., D. Kritchevsky, and P.P. Nair. 1988. The Bile Acids. Chemistry, Physiology and Metabolism. Volume 4: Methods and Applications. Plenum Press, New York/London. 582 pp.
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The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
Russell, D. W. (2003) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.72.121801.161712 · Cited by 2,069
Self-citationRole of Bile Acids and Bile Acid Receptors in Metabolic Regulation
Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., & Staels, B. (2009) · Physiological Reviews · doi:10.1152/physrev.00010.2008 · Cited by 1,678
Clinical importance of the cytochromes P450
Nebert, D. W., & Russell, D. W. (2002) · The Lancet · doi:10.1016/s0140-6736(02)11203-7 · Cited by 1,416
Self-citationBile Acid Metabolism and Signaling
Chiang, J. Y. L. (2013) · Comprehensive physiology · doi:10.1002/cphy.c120023 · Cited by 1,662
The Continuing Importance of Bile Acids in Liver and Intestinal Disease
Hofmann, A. F. (1999) · Archives of Internal Medicine · doi:10.1001/archinte.159.22.2647 · Cited by 972
Metadata
- Authors
- Setchell, K. D., Schwarz, M., O'Connell, N. C., Lund, E. G., Davis, D. L., Lathe, R., Thompson, H. R., Weslie Tyson, R., Sokol, R. J., & Russell, D. W.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- University of Edinburgh (GB)
- University of Colorado Denver (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1998-11-01
- Volume
- 102
- Issue
- 9
- Pages
- 1690-1703
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC509117
- OpenAlex
- W2123957814
- Cited by
- 375
- References
- 85
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 12 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 7 · 2019: 12 · 2018: 14 · 2017: 14 · 2016: 8 · 2015: 6 · 2014: 13 · 2013: 12 · 2012: 10
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Journal of Clinical Investigation (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- National Organization for Rare Disorders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (HL20948, RR00069)
- Directorate for Biological Sciences
- Medical Research Council
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-38446, R01DK038446)
- National Center for Research Resources (RROOO69, M01RR000069)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
- Keywords
- neonatal cholestasis, liver cirrhosis, 27-hydroxycholesterol, stop codon mutation, cholestatic liver disease
- MeSH terms
- Cytochrome P450 Family 7, Amino Acid Sequence, Animals, Base Sequence, Bile Acids and Salts, Cell Line, Transformed, Cytochrome P-450 Enzyme System, Cricetinae, Humans, Infant, Liver, Liver Diseases, Male, Metabolism, Inborn Errors, Microsomes, Liver, Molecular Sequence Data, Mutation, Steroid Hydroxylases, Sterols, Liver Transplantation, CHO Cells, DNA, Complementary, Cholic Acid
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