title: Characterisation of three novel CYP11B1 mutations in classic and non-classic 11β-hydroxylase deficiency.
abstract: BACKGROUND
  Congenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.
  
  
  OBJECTIVE
  The aim of the study was to study the functional consequences of three novel CYP11B1 gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype.
  
  
  METHODS
  Functional analyses were done by using a HEK293 cell in vitro expression system comparing WT with mutant P450c11 activity. Mutant proteins were examined in silico to study their effect on the three-dimensional structure of the protein.
  
  
  RESULTS
  Two mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity.
  
  
  CONCLUSIONS
  Functional mutation analysis enables the correlation of novel CYP11B1 mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.
authors.affiliation: Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
authors.forename: Seher
authors.initials: S
authors.lastname: Polat
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kulle
authors.forename: Züleyha
authors.initials: Z
authors.lastname: Karaca
authors.forename: Ilker
authors.initials: I
authors.lastname: Akkurt
authors.forename: Selim
authors.initials: S
authors.lastname: Kurtoglu
authors.forename: Fahrettin
authors.initials: F
authors.lastname: Kelestimur
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000328:Adult; D019943:Amino Acid Substitution; D002675:Child, Preschool; D019295:Computational Biology; D005103:Expert Systems; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D057809:HEK293 Cells; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012720:Severity of Illness Index; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D013252:Steroid 11-beta-Hydroxylase