New, recurrent, and prevalent mutations: Clinical and molecular characterization of 26 Chinese patients with 17alpha-hydroxylase/17,20-lyase deficiency.

BACKGROUND: Combined 17alpha-hydroxylase/17,20-lyase deficiency (17OHD), caused by mutations in the CYP17A1 gene, is a rare autosomal recessive form of congenital adrenal hyperplasia and characterized by hyporeninemic hypokalemic hypertension, primary amenorrhea and absence of secondary sexual characteristics.

SUBJECTS AND METHODS: Twenty six 17OHD subjects from 23 Chinese families were recruited. The CYP17A1 gene was sequenced and 17alpha-hydroxylase/17,20-lyase enzymatic activities were assessed in vitro.

RESULTS: Eight CYP17A1 mutations were identified in 23 patients. Of eight mutations, c.985_987delinsAA/p.Y329Kfs and c.1460_1469del/p.D487_F489del mutations accounted for 60.8% (28/46) and 21.7% (10/46) of the mutant alleles, respectively. The enzymatic activities for both mutations were completely abolished. We also identified three novel mutations c.971_972insG/p.K325Afx, c.1464_1466delT/p.F489Sfx and c.1386G>T/p.R462S. The enzymatic activities for c.971_972insG/p.K325Afx and c.1464_1466delT/p.F489Sfx mutations were almost completely abolished, whereas the mutation c.1386G>T/p.R462S only resulted in partial reduction of 17alpha-hydroxylase (34.6%) and 17,20 lyase activities (27.0%), which is correlated with the partial 17OHD phenotype in this patient.

CONCLUSION: The c.985_987delinsAA/p.Y329Kfs and c.1460_1469del/p.D487_F489del mutations are prevalent in Chinese 17OHD patients. The genetic defects are well correlated with the phenotypes in both complete and partial forms of 17OHD.