title: Phenotype-genotype correlations of 13 rare CYP21A2 mutations detected in 46 patients affected with 21-hydroxylase deficiency and in one carrier.
abstract: BACKGROUND
  Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with genotype/phenotype relationships for common mutations. Novel mutations of the CYP21A2 gene must be well studied to propose right genetic counseling for patients.
  
  
  OBJECTIVE
  Thirteen CYP21 mutations have been studied. A detailed description of phenotype was performed for all mutations (p.I77T, p.L167P, p.I230T, p.R233K, p.G291S, p.G292D, p.E320K, p.R341P, p.R354H, p.R369W, p.R408C, p.G424S, and p.R426H). In vitro and in silico studies were performed only for those not previously described (p.L167P, p.I230T, p.R233K, p.G292D, p.E320K, and p.R369W).
  
  
  RESULTS
  Regarding phenotype, patients with 10 of these mutations had a classical form. A patient with isolated p.I230T presented with nonclassical form and a patient with the association p.I230T + p.V281L in cis presented with a more severe phenotype. The p.R233K mutation was detected in a carrier partner. A patient with p.R369W presented with an intermediate form. Functional studies showed that all mutations except p.I230T and p.R369W decreased enzyme activity more than p.P30L: severity of p.R369W was intermediate between p.P30L and p.V281L, and finally p.I230T was less severe than p.V281L. Mutation analysis in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, severe mutations being implicated in important functional domains of the protein.
  
  
  CONCLUSIONS
  According to phenotype and functional studies, 11 of the mutations described, except the isolated p.R369W and p.I230T, may be responsible for a severe phenotype underlying the necessity to manage children having them. The p.I230T is a nonclassical mutation, and for the p.R369W, we need more cases to precise its severity.
authors.affiliation: Laboratoire d'Endocrinologie Moléculaire et Maladies Rares, Centre de Biologie et de Pathologie Est, 69677 Bron Cedex, France. veronique.tardy@chu-lyon.fr
authors.forename: V
authors.initials: V
authors.lastname: Tardy
authors.forename: R
authors.initials: R
authors.lastname: Menassa
authors.forename: V
authors.initials: V
authors.lastname: Sulmont
authors.forename: A
authors.initials: A
authors.lastname: Lienhardt-Roussie
authors.forename: C
authors.initials: C
authors.lastname: Lecointre
authors.forename: R
authors.initials: R
authors.lastname: Brauner
authors.forename: M
authors.initials: M
authors.lastname: David
authors.forename: Y
authors.initials: Y
authors.lastname: Morel
mesh_terms: D019326:17-alpha-Hydroxyprogesterone / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011487:Protein Conformation; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors
chemical_list: D019326:17-alpha-Hydroxyprogesterone; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase