M. Schwarz et al., The bile acid synthetic gene 3 beta-hydroxy-Delta(5)-C-27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis, J CLIN INV, 106(9), 2000, pp. 1175-1184
We used expression cloning to isolate cDNAs encoding a microsomal 3 beta -h
ydroxy-Delta (5)-C-27-steroid oxidoreductase (C-27 3 beta -HSD) that is exp
ressed predominantly in the liver. The predicted product shares 34% sequenc
e identity with the C-19 and C-21 3 beta -HSD enzymes, which participate in
steroid hormone metabolism. When transfected into cultured cells, the clon
ed C-27 3 beta -HSD cDNA encodes an enzyme that is active against four 7 al
pha -hydroxylated sterols, indicating that a single C-27 3 beta -HSD enzyme
can participate in all known pathways of bile acid synthesis. The expresse
d enzyme did not metabolize several different C-19/21 steroids as substrate
s. The levels of hepatic C-27 3 beta -HSD mRNA in the mouse are not sexuall
y dimorphic and do not change in response to dietary cholesterol or to chan
ges in bile acid pool size. The corresponding human gene on chromosome 16p1
1.2-12 contains six exons and spans 3 kb of DNA, and we identified a 2-bp d
eletion in the C-27 3 beta -HSD gene of a patient with neonatal progressive
intrahepatic cholestasis. This mutation eliminates the activity of the enz
yme in transfected cells. These findings establish the central role of C-27
3 beta -HSD in the biosynthesis of bile acids and provide molecular tools
for the diagnosis of a third type of neonatal progressive intrahepatic chol
estasis associated with impaired bile acid synthesis.