title: Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran.
abstract: OBJECTIVE
  Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders frequently caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). We describe three novel CYP21A2 mutations in CAH patients.
  
  
  METHODS
  Sequence analysis of the entire CYP21A2 gene followed by molecular modelling was performed in three unrelated classical CAH patients of northeastern Iranian origin. The active (CYP21A2) and pseudogene (CYP21A1P) alleles were screened for the presence of the new variations in controls.
  
  
  RESULTS
  Two novel missense mutations, F404S in exon 9 and T450P in exon 10, were found in homozygous forms in two female patients with a salt-wasting (SW) phenotype. These novel variants were screened by allele-specific polymerase chain reaction (PCR) and excluded in 100 unrelated normal alleles. Prediction of clinical severity, based on molecular modelling and sequence conservation, correlates well with the clinical diagnosis of the patients carrying these mutations. The third novel mutation, a small 10-bp deletion in exon 1, g.19_28del, was found in a female patient with a simple virilizing phenotype in a compound heterozygous form with the common intron 2 splice mutation (IVS2-13A/C>G). This frameshift mutation causes a premature stop codon at amino acid position 48, L48X, resulting in a nonfunctional protein. The CYP21A1P pseudogene alleles were also screened and none of these novel mutations could be detected.
  
  
  CONCLUSIONS
  Three novel mutations were found in the CYP21A2 gene and predicted to drastically impair enzyme activity resulting in severe classic CAH. None of these mutations occurs in the CYP21A1P pseudogene.
authors.affiliation: Division of Human Genetics, Immunology Research Centre, Bu-Ali Research Institute, Mashhad, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Baradaran-Heravi
authors.forename: Rahim
authors.initials: R
authors.lastname: Vakili
authors.forename: Tiina
authors.initials: T
authors.lastname: Robins
authors.forename: Jonas
authors.initials: J
authors.lastname: Carlsson
authors.forename: Nosrat
authors.initials: N
authors.lastname: Ghaemi
authors.forename: Azadeh
authors.initials: A
authors.lastname: A'rabi
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Abbaszadegan
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007492:Iran; D020125:Mutation, Missense; D010375:Pedigree; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013255:Steroid 21-Hydroxylase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase