Journal of Clinical Endocrinology & Metabolism, Vol 79, 160-164, Copyright © 1994 by Endocrine Society

ARTICLES

Point mutation of Arg440 to His in cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency

CE Fardella, DW Hum, J Homoki and WL Miller
Department of Pediatrics, University of California, San Francisco 94143.

Genetic disorders in the gene encoding P450c17 cause 17 alpha- hydroxylase deficiency. The consequent defects in the synthesis of cortisol and 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 development and mild hypertension with hypokalemia, high concentrations of 17-deoxysteroids, and hypergonadotropic hypogonadism. Analysis of her P450c17 gene by polymerase chain reaction amplification and direct sequencing showed mutation of codon 440 from CGC (Arg) to CAC (His). Expression of a vector encoding this mutated form of P450c17 in transfected nonsteroidogenic COS-1 cells showed that the mutant P450c17 protein was produced, but it lacked both 17 alpha-hydroxylase and 17,20-lyase activities. To date, 15 different P450c17 mutations have been described in 23 patients with 17 alpha-hydroxylase deficiency, indicating that mutations in this gene are due to random events.

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