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The genetic and functional basis of isolated 17, 20-lyase deficiency

Abstract:

Human male sexual differentiation requires production of fetal testicular testosterone, whose biosynthesis requires steroid 17, 20-lyase activity1, 2. Patients with putative isolated 17, 20-lyase deficiency have been reported3, 4. The existence of true isolated 17, 20-lyase deficiency, however, has been questioned because 17α-hydroxylase and 17, 20-lyase activities are catalyzed by a single enzyme5-8, microsomal cytochrome P450c17, and because the index case of apparent isolated 17, 20-lyase deficiency had combined deficiencies of both activities9, 10. We studied two patients with clinical and hormonal findings suggestive of isolated 17, 20-lyase deficiency. We found two patients homozygous for substitution mutations in CYP17, the gene encoding P450c17. When expressed in COS-1 cells, the mutants retained 17α-hydroxylase activity but had minimal 17, 20-lyase activity. Substrate competition experiments suggested that the mutations did not alter the enzyme’s substrate-binding capacity, but co-transfection of cells with P450 oxidoreductase, the electron donor used by P450c17, indicated that the mutants had a diminished ability to interact with redox partners. Computer-graphic modelling of P450c17 suggests that both mutations lie in or near the redox-partner binding site, on the opposite side of the haem from the substrate-binding pocket. These mutations alter electrostatic charge distribution in the redox-partner binding site, so that electron transfer for the 17, 20-lyase reaction is selectively lost or diverted to uncoupling reactions. These are the first proven cases of isolated 17, 20-lyase deficiency, and they demonstrate a novel mechanism for loss of enzymatic activity. © 1997 Nature Publishing Group.