title: A novel homozygous mutation in CYP11A1 gene is associated with late-onset adrenal insufficiency and hypospadias in a 46,XY patient.
abstract: BACKGROUND
  The first and the rate-limiting step in the biosynthesis of hormones in all steroidogenic tissues, conversion of cholesterol to pregnenolone, is catalyzed by the cholesterol side-change cleavage cytochrome P450 (P450scc) encoded by a single gene, CYP11A1. To date, mutations in CYP11A1 gene have been reported in six patients, all of whom presented with adrenal insufficiency within the first 4 yr of life and severely underandrogenized external genitalia (Prader stages 1-2).
  
  
  OBJECTIVE
  Our aim was to characterize in vitro and in vivo effects of a novel homozygous CYP11A1 gene mutation identified in a patient with an unusual presentation of P450scc deficiency.
  
  
  METHODS
  A 46,XY patient presented with mid-shaft hypospadias and cryptorchidism at birth and signs of adrenal failure at 9 yr. Mutational analysis of CYP11A1 gene was performed by PCR, followed by direct sequencing. P450scc activity was determined by measuring concentration of pregnenolone synthesized from cholesterol in the medium after a transient transfection of HEK293 cells with P450scc, adrenodoxin, adrenodoxin reductase, and steroidogenic acute regulatory protein expression plasmids.
  
  
  RESULTS
  The sequencing of CYP11A1 gene in the proband revealed a novel homozygous L222P mutation, whereas both parents were heterozygous carriers for this mutation. In vitro P450scc activity of L222P mutant was approximately 7% compared with the wild type.
  
  
  CONCLUSIONS
  This case represents the mildest phenotype of P450scc deficiency to be described. The phenotypic presentation was consistent with the partial reduction of P450scc activity of L222P mutant.
authors.affiliation: Department of Endocrine Genetics, Endocrinology Research Center, Moscow 117036, Russian Federation.
authors.forename: Petr
authors.initials: P
authors.lastname: Rubtsov
authors.forename: Maksim
authors.initials: M
authors.lastname: Karmanov
authors.forename: Polina
authors.initials: P
authors.lastname: Sverdlova
authors.forename: Pavel
authors.initials: P
authors.lastname: Spirin
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tiulpakov
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D002648:Child; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics*; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007021:Hypospadias / Q000235:genetics*; D008297:Male; D009154:Mutation; D010750:Phosphoproteins / Q000172:deficiency; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D002786:Cholesterol Side-Chain Cleavage Enzyme