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

J Clin Invest. 1998 Nov 1;102(9):1690-703. doi: 10.1172/JCI2962.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Bile Acids and Salts / biosynthesis*
  • Bile Acids and Salts / blood
  • CHO Cells
  • Cell Line, Transformed
  • Cholic Acid / therapeutic use
  • Cricetinae
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Cytochrome P450 Family 7
  • DNA, Complementary
  • Humans
  • Infant
  • Liver / pathology
  • Liver Diseases / drug therapy
  • Liver Diseases / enzymology*
  • Liver Diseases / genetics
  • Liver Transplantation
  • Male
  • Metabolism, Inborn Errors / drug therapy
  • Metabolism, Inborn Errors / enzymology*
  • Metabolism, Inborn Errors / genetics
  • Microsomes, Liver / enzymology
  • Molecular Sequence Data
  • Mutation*
  • Steroid Hydroxylases / genetics*
  • Steroid Hydroxylases / metabolism
  • Sterols / blood
  • Sterols / urine


  • Bile Acids and Salts
  • DNA, Complementary
  • Sterols
  • Cytochrome P-450 Enzyme System
  • Steroid Hydroxylases
  • oxysterol 7-alpha-hydroxylase
  • Cytochrome P450 Family 7
  • CYP7B1 protein, human
  • Cholic Acid

Associated data

  • GENBANK/AF029403