Molecular basis of 17α-hydroxylase/17,20-lyase deficiency

17α-Hydroxylase deficiency is characterized by a defect in either or both of 17α-hydroxylase and 17,20-lyase activities, based on the fact that a single polypeptide P450c17 can catalyze both reactions. The clinical manifestations of 17α-hydroxylase/17,20-lyase deficiency seem to be more heterogeneous than expected, varying from the classical type to less symptomatic forms as also observed in 21-hydroxylase deficiency. We have sequenced all eight exons of the CYP17 (P450c17) gene in DNA from several patients, reconstructed the mutations in a human P450c17 cDNA and expressed the mutant P450c17 in COS 1 cells to characterize the kinetic properties of 17α-hydroxylase and 17,20-lyase activities. The molecular bases of cases clinically reported as 17α-hydroxylase deficiency have turned out to be complete or partial combined deficiencies of 17α-hydroxylase/17,20-lyase. The elucidation of the molecular basis generally explains the patient's clinical profiles including the sexual phenotype of the external genitalia. In one case clinically reported as isolated 17,20-lyase deficiency, the molecular basis was found to be partial combined deficiency of both activities, somewhat discordant with the patient's clinical profile. Based on the results obtained so far we can predict that those 17α-hydroxylase deficient individuals having a homozygous stop codon in the CYP17 gene positioned at the amino terminal side of the P450c17 heme-binding cysteine (442) will all have the same phenotype. However those individuals having homozygous missense mutations or those who are compound heterozygotes having a missense mutation in at least one CYP17 allele will display their own unique phenotype which clinically will be subtly different from all others.