title: Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency.
abstract: BACKGROUND
  Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Cases of nonclassic 11OHD are rare compared with the incidence of nonclassic 21-hydroxylase deficiency.
  
  
  OBJECTIVE
  The aim of the study was to analyze the functional consequences of seven novel CYP11B1 mutations (p.M88I, p.W116G, p.P159L, p.A165D, p.K254_A259del, p.R366C, p.T401A) found in three patients with classic 11OHD, two patients with nonclassic 11OHD, and three heterozygous carriers for CYP11B1 mutations.
  
  
  METHODS
  We conducted functional studies employing a COS7 cell in vitro expression system comparing wild-type (WT) and mutant CYP11B1 activity. Mutants were examined in a computational three-dimensional model of the CYP11B1 protein.
  
  
  RESULTS
  All mutations (p.W116G, p.A165D, p.K254_A259del) found in patients with classic 11OHD have absent or very little 11beta-hydroxylase activity relative to WT. The mutations detected in patients with nonclassic 11OHD showed partial functional impairment, with one patient being homozygous (p.P159L; 25% of WT) and the other patient compound heterozygous for a novel mild p.M88I (40% of WT) and the known severe p.R383Q mutation. The two mutations detected in heterozygous carriers (p.R366C, p.T401A) also reduced CYP11B1 activity by 23 to 37%, respectively.
  
  
  CONCLUSIONS
  Functional analysis results allow for the classification of novel CYP11B1 mutations as causative for classic and nonclassic 11OHD, respectively. Four partially inactivating mutations are predicted to result in nonclassic 11OHD. These findings double the number of mild CYP11B1 mutations previously described as associated with mild 11OHD. Our data are important to predict phenotypic expression and provide important information for clinical and genetic counseling in 11OHD.
authors.affiliation: Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Institute of Biomedical Research, Wolfson Drive, Birmingham B15 2TT, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parajes
authors.forename: Lourdes
authors.initials: L
authors.lastname: Loidi
authors.forename: Nicole
authors.initials: N
authors.lastname: Reisch
authors.forename: Vivek
authors.initials: V
authors.lastname: Dhir
authors.forename: Ian T
authors.initials: IT
authors.lastname: Rose
authors.forename: Rainer
authors.initials: R
authors.lastname: Hampel
authors.forename: Marcus
authors.initials: M
authors.lastname: Quinkler
authors.forename: Gerard S
authors.initials: GS
authors.lastname: Conway
authors.forename: Lidia
authors.initials: L
authors.lastname: Castro-Feijóo
authors.forename: David
authors.initials: D
authors.lastname: Araujo-Vilar
authors.forename: Manuel
authors.initials: M
authors.lastname: Pombo
authors.forename: Fernando
authors.initials: F
authors.lastname: Dominguez
authors.forename: Emma L
authors.initials: EL
authors.lastname: Williams
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Cole
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Kirk
authors.forename: Elke
authors.initials: E
authors.lastname: Kaminsky
authors.forename: Gill
authors.initials: G
authors.lastname: Rumsby
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Nils
authors.initials: N
authors.lastname: Krone
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000328:Adult; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D013252:Steroid 11-beta-Hydroxylase