At least 17 mutations in the HSD3B7 gene have been found to cause congenital bile acid synthesis defect type 1. This condition is characterized by cholestasis, a condition that impairs the production and release of a digestive fluid called bile from liver cells. Most of the HSD3B7 gene mutations delete one or two DNA building blocks (base pairs) from the gene or replace single protein building blocks (amino acids) in the enzyme. These mutations result in production of a 3β-HSD7 enzyme with little or no function. Without enough functional 3β-HSD7 enzyme, the conversion of 7α-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one is impaired. The 7α-hydroxycholesterol instead gets converted into abnormal bile acid compounds that cannot be transported out of the liver into the intestine, where the bile acids are needed to absorb fats and fat-soluble vitamins. This impaired production and release of bile acids leads to cholestasis. As a result, cholesterol and abnormal bile acids build up in the liver and fat-soluble vitamins are not absorbed, leading to the signs and symptoms of congenital bile acid synthesis defect type 1.
At least 37 mutations in the HSD3B2 gene have been found to cause 3β-HSD deficiency. Most of these mutations change single protein building blocks (amino acids) in the 3β-HSD enzyme, which typically reduces the activity of the enzyme. Mutations that allow the production of some functional enzyme, although at reduced levels, cause the less severe, non-salt-wasting or non-classic forms of 3β-HSD deficiency. Other mutations result in the production of an abnormally short, completely nonfunctional 3β-HSD enzyme, which causes the more severe, salt-wasting form of this condition. All types of 3β-HSD deficiency interfere with the production of a variety of hormones and lead to abnormalities of sexual development and maturation.
The enzyme converting 5-cholestene-3 beta, 7 alpha-diol to 7 alpha-hydroxy-4-cholesten-3-one has been solubilized from rabbit liver microsomes by treatment with a mixture of sodium cholate and the nonionic detergent Renex 690. The enzyme was purified about 200-fold, with a recovery of more than 50%, by chromatography on DEAE-cellulose, hydroxylapetite, 2',5',ADP-Sepharose 4B and 5'-AMP-Sepharose 4B. The purified enzyme showed only one protein band, with an apparent molecular weight of 46,000, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme was eluted as a single peak on gel filtration on Ultrogel AcA 34. The elution volume corresponded to that observed for globular proteins with molecular weights in the 45,000 to 50,000 region. The substrate specificity of the microsomal fraction and of the purified oxidoreductase in oxidation and reduction of various 3-oxygenated C19-, C21-, and C27-steroids was studied in the presence of NAD and NADH. Whereas the microsomal fraction had a broad substrate specificity, NAD-supported oxidation with the purified oxidoreductase only occurred with 5-cholestene-3 beta, 7 alpha-diol as substrate. NADP could not replace NAD in the reaction. NADH-supported reduction with the purified oxidoreductase only occurred with 7 alpha-hydroxy-5 alpha-cholestan-3-one as substrate. The results suggest that conversion of 5-cholestene-3 beta, 7 alpha-diol to 7 alpha-hydroxy-4-cholesten-3-one is catalyzed by a single enzyme specific for certain C27-steroids.