title: Genetic screening of non-classic CAH females with hyperandrogenemia identifies a novel CYP11B1 gene mutation.
abstract: OBJECTIVE
  Congenital adrenal hyperplasia (CAH) is an endocrine autosomal recessive disorder with various symptoms of diverse severity. Mild hyperandrogenemia is the most commonclinical feature in non-classic CAH patients and 95% of the cases are identified by mutations in the CYP21A2 gene. In the present study, the second most common cause for non-classic CAH (NC-CAH), 11β-hydroxylase deficiency due to mutations in the CYP11B1 gene, is investigated.
  
  
  METHODS
  Screening of the CYP21A2 and CYP11B1 genes by direct sequencing was carried out for the detection of possible genetic defects in patients with suspected CAH.
  
  
  RESULTS
  It wasobserved that CYP11B1 variants co-exist only in rare cases along with mutations in CYP21A2 in patients clinically diagnosed with CAH. A total of 23 NC-CAH female patients out of 75 were identified with only one mutation in the CYP21A2 gene. The novel CYP11B1 gene mutation, p.Val484Asp, was identified in a patient with CAH in the heterozygous state. The structural characterization of the novel p.Val484Asp was found to likely cause distortion of the surrounding beta sheet and indirect destabilization of the cavity that occurs on the opposite face of the structural elements, leading to partial impairment of the enzymatic activity.
  
  
  CONCLUSIONS
  CYP21A2 gene mutations are the most frequent genetic defects in cases of NC-CAH even when these patients are in the heterozygous state. These mutations have a diverse phenotype giving rise to a variable extent of cortisol synthesis impairment; it is also clear that CYP11B1 mutants are a rare type of defects causing CAH.
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, 1683, Nicosia, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Christos
authors.initials: C
authors.lastname: Shammas
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, 1683, Nicosia, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Stefania
authors.initials: S
authors.lastname: Byrou
authors.affiliation: NMR Centre for Structural Biology, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Marie M
authors.initials: MM
authors.lastname: Phelan
authors.affiliation: Division of Pediatrics, Iasis Hospital, Pafos, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Meropi
authors.initials: M
authors.lastname: Toumba
authors.affiliation: Pediatric Endocrinology, Pafos General Hospital, Pafos, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Charilaos
authors.initials: C
authors.lastname: Stylianou
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, 1683, Nicosia, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Nicos
authors.initials: N
authors.lastname: Skordis
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, 1683, Nicosia, Cyprus.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus.
authors.forename: Vassos
authors.initials: V
authors.lastname: Neocleous
authors.affiliation: Department of Molecular Genetics, Function & Therapy, The Cyprus Institute of Neurology & Genetics, 1683, Nicosia, Cyprus. laphylac@cing.ac.cy.|St George's, University of London Medical School at the University of Nicosia, Nicosia, Cyprus. laphylac@cing.ac.cy.
authors.forename: Leonidas A
authors.initials: LA
authors.lastname: Phylactou
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D004795:Enzyme Stability; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006579:Heterozygote; D006801:Humans; D017588:Hyperandrogenism / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D000072757:Protein Conformation, beta-Strand; D013252:Steroid 11-beta-Hydroxylase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase