Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.
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.
Setchell
K D
KD
Clinical Mass Spectrometry Center, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. setck0@chmcc.org
Schwarz
M
M
O'Connell
N C
NC
Lund
E G
EG
Davis
D L
DL
Lathe
R
R
Thompson
H R
HR
Weslie Tyson
R
R
Sokol
R J
RJ
Russell
D W
DW
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000097:blood; D016466:CHO Cells; D002461:Cell Line, Transformed; D019826:Cholic Acid / Q000627:therapeutic use; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072474:Cytochrome P450 Family 7; D018076:DNA, Complementary; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D016031:Liver Transplantation; D008297:Male; D008661:Metabolism, Inborn Errors / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D009154:Mutation; D013250:Steroid Hydroxylases / Q000235:genetics* / Q000378:metabolism; D013261:Sterols / Q000097:blood / Q000652:urine
D001647:Bile Acids and Salts; D018076:DNA, Complementary; D013261:Sterols; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C115867:oxysterol 7-alpha-hydroxylase; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human; D019826:Cholic Acid