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

CONTEXT: The CYP17A1 gene encodes many enzymatic reactions including 17alpha-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 17alpha-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 (C(19)-steroids) pointing to the absence of 17,20-lyase activities. Furthermore, precursor/product ratios of urinary steroid metabolites characterizing 17alpha-hydroxylase activity showed variable decreases in 17alpha-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 17alpha-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 17alpha-hydroxylase activity.