Identification of a new inborn error in bile acid synthesis: Mutation of the oxysterol 7 alpha-hydroxylase gene causes severe neonatal liver disease

K D R Setchell, M Schwarz, N C O'Connell, E G Lund, D L Davis, R Lathe, H R Thompson, R W Tyson, R J Soko, D W Russell

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7 alpha-hydroxylation due to a mutation in the gene for the microsomal oysterol 7 alpha-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 produces of hepatic synthesis to be 3 beta-hydroxy-5-cholenoic and 3 beta-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 7 alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids, Hepatic microsomal oxysterol 7 alpha-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.

Original languageEnglish
Pages (from-to)1690-1703
Number of pages14
JournalJournal of Clinical Investigation
Issue number9
Publication statusPublished - 1 Nov 1998

Keywords / Materials (for Non-textual outputs)

  • Amino Acid Sequence
  • animals
  • Base Sequence
  • bile acids and salts
  • CHO Cells
  • Cell Line, Transformed
  • Cholic acid
  • Cricetinae
  • Cytochrome P-450 Enzyme System
  • DNA, Complementary
  • Humans
  • Infant
  • Liver/pathology
  • Liver Diseases
  • Liver Transplantation
  • Male
  • Metabolism, Inborn Errors
  • Microsomes, Liver
  • Molecular Sequence Data
  • Mutation
  • Steroid Hydroxylases
  • Sterols


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