POINT MUTATION OF ARG440 TO HIS IN CYTOCHROME P450C17 CAUSES SEVERE 17-ALPHA-HYDROXYLASE DEFICIENCY

Genetic disorders in the gene encoding P450c17 cause 17 alpha-hydroxyl ase deficiency. The consequent defects in the synthesis of cortisol an d sex steroids cause sexual infantilism and a female phenotype in both genetic sexes as well as mineralocorticoid excess and hypertension. A 15-yr-old patient from Germany was seen for absent pubertal developme nt and mild hypertension with hypokalemia, high concentrations of 17-d eoxysteroids, and hypergonadotropic hypogonadism. Analysis of her P450 c17 gene by polymerase chain reaction amplification and direct sequenc ing showed mutation of codon 440 from CGC (Arg) to CAC (His). Expressi on of a vector encoding this mutated form of P450c17 in transfected no nsteroidogenic COS-1 cells showed that the mutant P450c17 protein was produced, but it lacked both 17 alpha-hydroxylase and 17,20-lyase acti vities. To date, 15 different P450c17 mutations have been described in 23 patients with 17 alpha-hydroxylase deficiency, indicating that mut ations in this gene are due to random events.