title: Clinical, genetic and functional characteristics of three novel CYP17A1 mutations causing combined 17alpha-hydroxylase/17,20-lyase deficiency.
abstract: BACKGROUND
  P450c17 has two distinct activities: 17alpha-hydroxylase activity and 17,20-lyase activity. Combined 17alpha-hydroxylase/17,20-lyase deficiency leads to a severe defect in the production of cortisol and sex steroids. In affected males this results in impaired masculinization with ambiguous or female external genitalia. Female patients have normal genitalia but show a lack of pubertal development in adolescence. An increased production of mineralocorticoids often leads to hypertension and hypokalemia in both sexes.
  
  
  METHODS
  To better understand the mechanisms of P450c17 deficiency, we studied 2 patients (both 46,XY) with combined 17alpha-hydroxylase/17,20-lyase deficiency of different severity: one with complete lack of masculinization and one with ambiguous genitalia.
  
  
  RESULTS
  Four mutations were identified by sequencing of the CYP17A1 gene: I332T and A355T in the less severely affected patient; G111S and R440H in the patient with complete lack of masculinization. The three novel mutations were expressed in COS1 cells and all mutant proteins except I332T showed a complete loss of both enzymatic activities. I332T retained some residual 17alpha-hydroxylase as well as 17,20-lyase activity.
  
  
  CONCLUSIONS
  We identified 2 patients with the phenotypical spectrum of P450c17 deficiency. Three novel mutations in the CYP17A1 gene were identified and their functional characterization provided a good phenotype-genotype correlation. The location of the mutated residues in the three-dimensional model of P450c17 gave some additional insights into its structure-function relationship.
authors.affiliation: University Children's Hospital, Zurich, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Rosa
authors.forename: M
authors.initials: M
authors.lastname: Steigert
authors.forename: M
authors.initials: M
authors.lastname: Lang-Muritano
authors.forename: D
authors.initials: D
authors.lastname: l'Allemand
authors.forename: E J
authors.initials: EJ
authors.lastname: Schoenle
authors.forename: A
authors.initials: A
authors.lastname: Biason-Lauber
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D056726:Genetic Association Studies; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase