title: A homozygous L299P mutation in the CYP11B1 gene leads to complete virilization in 46,XX individuals with 11-beta-hydroxylase deficiency.
abstract: OBJECTIVE
  11-beta-hydroxylase deficiency (11betaOHD) is caused by CYP11B1 gene defects and leads to congenital adrenal hyperplasia associated with hypertension. Recently, a novel L299P mutation has been described in a compound heterozygous male individual. We observed two 46,XX siblings with a homozygous L299P mutation and investigated the functional properties of this CYP11B1 variant.
  
  
  METHODS
  The index patient from a consanguineous Turkish family showed complete external virilization and was diagnosed incidentally at the age of 19 months during hospital admission for severe combined bacterial (urosepsis) and viral (CMV and EBV) infection. The younger sibling was diagnosed at the age of 5 months. Their genital phenotype was identical and both demonstrated borderline elevated blood pressure.
  
  
  RESULTS
  Biochemical findings revealed 11betaOHD. A homozygous L299P mutation of the CYP11B1 gene was detected. In vitro expression studies performed in HCT116 cells showed a markedly decreased CYP11B1 activity in the L299P mutant (1.6 +/- 0.8%) for the conversion of 11-deoxycortisol to cortisol.
  
  
  CONCLUSIONS
  Our study provides clear data on the functional properties and clinical phenotype in 46,XX individuals homozygous for this point mutation. Adrenal insufficiency might have contributed to the severe infectious disease that was present in the index patient at diagnosis.
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria. stefan.riedl@meduniwien.ac.at
authors.forename: Stefan
authors.initials: S
authors.lastname: Riedl
authors.forename: Huy-Hoang
authors.initials: HH
authors.lastname: Nguyen
authors.forename: Susanne
authors.initials: S
authors.lastname: Clausmeyer
authors.forename: Egbert
authors.initials: E
authors.lastname: Schulze
authors.forename: Franz
authors.initials: F
authors.lastname: Waldhauser
authors.forename: Rita
authors.initials: R
authors.lastname: Bernhardt
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D003350:Cortodoxone / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000235:genetics; D005260:Female; D023961:Gonadal Dysgenesis, 46,XX / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D007223:Infant; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014770:Virilism / Q000201:enzymology / Q000235:genetics*
chemical_list: D004247:DNA; D013252:Steroid 11-beta-Hydroxylase; D003350:Cortodoxone