Hereditary male pseudohermaphroditism associated with an unstable form of 5 alpha-reductase.

The properties of 5alpha-reductase have been compared in genital skin fibroblasts cultured from five patients from three families (Los Angeles, Dallas, and Dominican Republic) in which hereditary male pseudohermaphroditism has been established to result from deficient conversion of testosterone to dihydrotestosterone. Despite the fact that 5alpha-reductase was immeasurable in a homogenate of epididymis removed from one of the Los Angeles patients, 5alpha-reductase activity was normal in intact fibroblasts and fibroblast extracts from both patients from the Los Angeles family. Although the apparent K(m) for testosterone was also near normal, the apparent K(m) for NADPH in these mutants is elevated some 40-fold above normal. Furthermore, the enzyme is not protected against denaturation at 45 degrees C by concentrations of NADPH that stabilize normal 5alpha-reductase, and in intact fibroblasts from these patients (but not from controls), enzyme activity decreases promptly when protein synthesis is inhibited. We conclude that the mutation in this family results in an unstable enzyme. In contrast 5alpha-reductase activity in fibroblast extracts from a patient from the Dominican Republic family is similar to that previously described in two members of the Dallas family, namely total enzyme activity is low at the optimal pH for the normal reaction, and the apparent K(m) for testosterone is some 20-fold higher than that of the controls. We conclude that the mutations in the Dallas and Dominican Republic families are similar and result in low activity of the enzyme as the result of a decreased affinity for testosterone.Thus, two distinct types of mutations can produce male pseudohermaphroditism due to deficient dihydrotestosterone formation.