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Metabolic evidence for impaired 17-hydroxylase activity in a kindred bearing the E305G mutation for isolate 17,20-lyase activity

¹ Pediatric Endocrinology, ² Metabolic Biochemistry Laboratory and ³ Genetics Institute, Rambam Medical Center, Meyer Children's Hospital, Technion-Israel Institute of Technology, 9602 Haifa, Israel⁴ Endocrine Clinic, Clalit Health Services, 9602 Haifa, Israel and ⁵ Steroid Research Unit, Center of Child and Adolescent Medicine, Justus Liebig University, Feulgenstr. 12, D-35392 Gießen, Germany

(Correspondence should be addressed to D Tiosano; Email: d_tiosano{at}rambam.health.gov.il)

Context: The CYP17A1 gene encodes many enzymatic reactions including 17-hydroxylase and 17,20-lyase activities. Mutations that selectively ablate the 17,20-lyase activity, causing isolated 17,20-lyase deficiency, are exceedingly rare and may belong to the rarest of all disorders of steroidogenesis. We have previously reported an E305G mutation in the active site of CYP17A1 that apparently causes isolated 17,20-lyase deficiency. Expression studies suggested intact 17-hydroxylase activity which was at odds with subnormal tetracosactrin stimulated cortisol in the patients.

Objectives: To investigate the in vivo activity of the adrenal enzymes, we used the metabolomics approach with urinary steroid profiling by gas chromatography–mass spectrometry.

Patients: Of the 11 subjects investigated, 6 patients in the kindred were found to be homozygous, 4 members were asymptomatic heterozygous, and 1 was homozygous for the wild-type allele.

Results: In the homozygous patients for E305G, both serum and urinary steroids showed a severe lack of androgens (C₁₉-steroids) pointing to the absence of 17,20-lyase activities. Furthermore, precursor/product ratios of urinary steroid metabolites characterizing 17-hydroxylase activity showed variable decreases in 17-hydroxylase activities.

Conclusions: The results confirm the complete absence of 17,20-lyase activity in vivo, as in the in vitro expression studies. On the other hand, in vivo 17-hydroxylase activity was partially impaired. Thus, the in vivo metabolic data seem to be more sensitive than the expression study and suggests that this mutation also impairs 17-hydroxylase activity.