STRUCTURE-FUNCTION-RELATIONSHIPS OF 3-BETA-HYDROXYSTEROID DEHYDROGENASE - CONTRIBUTION MADE BY THE MOLECULAR-GENETICS OF 3-BETA-HYDROXYSTEROID DEHYDROGENASE-DEFICIENCY

The transformation of Delta 5-3 beta-hydroxysteroids into the correspo nding Delta 4-3-keto-steroids is an essential step for the biosynthesi s of all classes of active steroids: progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. These steroid hormones pla y a crucial role in the differentiation, development, growth, and phys iological function of most human tissues. The structures of several cD NAs encoding 3 beta-HSD isoenzymes have been characterized in human an d several other vertebrate species: human types I and II; macaque; bov ine; rat types I, II, III and IV; mouse types I, II, III, IV, V, and V I; hamster types I, II, and III; and rainbow trout. Their transient ex pression reveals that 3 beta-HSD and Delta 5-Delta 4-isomerase activit ies reside within a single protein. Distinct approaches have been used for a better understanding of the structure-function relationships of these 3 beta-HSD enzymes: i) affinity radiolabeling studies of the hu man type I 3 beta-HSD; ii) identification and the functinoal consequen ces of the human type-II 3 beta-HSD mutations detected in patients wit h 3 beta-HSD deficiency. Taken together, all of these data were examin ed to determine whether the relationship between the genotype and the phenotype of these patients were consistent with in vitro mutagenesis studies. 3 beta-HSD deficiency, transmitted in an autosomic recessive disorder, is characterized by varying degrees of salt wasting; in gene tic males, fetal testicular 3 beta-HSD deficiency causes an underviril ized male genitalia (male pseudohermaphroditism); females exhibit eith er normal sexual differentiation of mild virilization. All mutations w ere detected in the type II 3 beta-HSD gene, which is expressed almost exclusively in the adrenals and gonads. No mutation was detected in t he type I 3 beta-HSD gene, which is expressed in peripheral tissues. T he finding of a normal type I 3 beta-HSD gene explains the elevated De lta 5-steroids and mild virilization of affected girls at birth. To da te, 24 mutations have been identified in 25 distinct families with 3 b eta-HSD deficiencies. All nonsense and frameshift mutations introducin g a premature termination codon were associated with the classical sal t-losing form. The locations of these nonsense mutations suggests that at least the firs 318 amino acids out of 371 are required for 3 beta- HSD activity. The consequences of the missense mutations on some domai ns of the 3 beta-enzyme, such as membrane-spanning domains, cofactor-b inding site, and steroid-binding site, were reviewed. The future cryst allization of the overexpressed normal and mutant-type II-3 beta-HSD e nzymes should contribute to a better understanding of the structure-fu nction relation-ships of the enzyme, especially for missense mutations located outside the putative functional regions. (C) 1997 by Elsevier Science Inc.