Identification of a new inborn error in bile acid synthesis

Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease

Kenneth D R Setchell, Margrit Schwarz, Nancy C. O'Connell, Erik G. Lund, Daphne L. Davis, Richard Lathe, Henry R. Thompson, R. Weslie Tyson, Ronald J. Sokol, David W. Russell

Research output: Contribution to journalArticle

254 Citations (Scopus)

Abstract

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7α-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7α-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 3β-hydroxy-5-cholenoic and 3β-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 7α-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7α-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 (US)
Pages (from-to)1690-1703
Number of pages14
JournalJournal of Clinical Investigation
Volume102
Issue number9
StatePublished - Nov 1 1998

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Infant, Newborn, Diseases
Mixed Function Oxygenases
Bile Acids and Salts
Liver Diseases
Mutation
Genes
Hydroxylation
Fast Atom Bombardment Mass Spectrometry
Terminator Codon
Liver
Cytosine
Cholestasis
Liver Failure
Oxysterols
Codon
Gas Chromatography
Thymidine
Sulfates
Arginine
Exons

Keywords

  • Cholestasis
  • Cholesterol metabolism
  • Genetics
  • Mass spectrometry

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Identification of a new inborn error in bile acid synthesis : Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease. / Setchell, Kenneth D R; Schwarz, Margrit; O'Connell, Nancy C.; Lund, Erik G.; Davis, Daphne L.; Lathe, Richard; Thompson, Henry R.; Tyson, R. Weslie; Sokol, Ronald J.; Russell, David W.

In: Journal of Clinical Investigation, Vol. 102, No. 9, 01.11.1998, p. 1690-1703.

Research output: Contribution to journalArticle

Setchell, KDR, Schwarz, M, O'Connell, NC, Lund, EG, Davis, DL, Lathe, R, Thompson, HR, Tyson, RW, Sokol, RJ & Russell, DW 1998, 'Identification of a new inborn error in bile acid synthesis: Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease', Journal of Clinical Investigation, vol. 102, no. 9, pp. 1690-1703.
Setchell, Kenneth D R ; Schwarz, Margrit ; O'Connell, Nancy C. ; Lund, Erik G. ; Davis, Daphne L. ; Lathe, Richard ; Thompson, Henry R. ; Tyson, R. Weslie ; Sokol, Ronald J. ; Russell, David W. / Identification of a new inborn error in bile acid synthesis : Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease. In: Journal of Clinical Investigation. 1998 ; Vol. 102, No. 9. pp. 1690-1703.
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abstract = "We describe a metabolic defect in bile acid synthesis involving a deficiency in 7α-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7α-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 3β-hydroxy-5-cholenoic and 3β-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 7α-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7α-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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AU - Setchell, Kenneth D R

AU - Schwarz, Margrit

AU - O'Connell, Nancy C.

AU - Lund, Erik G.

AU - Davis, Daphne L.

AU - Lathe, Richard

AU - Thompson, Henry R.

AU - Tyson, R. Weslie

AU - Sokol, Ronald J.

AU - Russell, David W.

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N2 - We describe a metabolic defect in bile acid synthesis involving a deficiency in 7α-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7α-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 3β-hydroxy-5-cholenoic and 3β-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 7α-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7α-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.

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