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Combined 17-Hydroxylase and 17,20-Desmolase Deficiencies: Evidence for Synthesis of a Defective Cytochrome P450_c17^*

Department of Pediatrics, University of Manitoba (J.S.D.W., R.M.C., J.M., Y.S.P.) Winnipeg, Manitoba
The Department of Pediatrics, University of Alberta (P.F., L.B.), Edmonton Alberta, Canada
The Children’s Hospital Medical Center of Northern California (C.H.L.S.) Oakland, California 94609

Address all correspondence and requests for reprints to: Dr. J. S. D. Winter, Section of Endocrinology and Metabolism, Children’s Hospital, AE105-840 Sherbrook Street, Winnipeg, Manitoba, Canada R3A 1S1.

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46, XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450_c17, Northern blot analysis demonstrated abundant amounts of RNA in these testes that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450_c17. These results suggest that these patients have a point mutation in the gene for P450_c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.

^* This work was supported by grants and fellowship support from the Medical Research Council of Canada, Children’s Hospital Research Foundation, St. Boniface Hospital Research Foundation, Manitoba Health Research Foundation, NIH and the Danish Medical Research Council. Presented in part to the 68th Annual Meeting of The Endocrine Society, Anaheim, CA, June 1986.

Received April 27, 1988.

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