title: Partial defect in the cholesterol side-chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia.
abstract: BACKGROUND
  The cholesterol side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene, converts cholesterol to pregnenolone to initiate steroidogenesis. Genetic defects in P450scc cause a rare autosomal recessive disorder that is clinically indistinguishable from congenital lipoid adrenal hyperplasia (lipoid CAH). Nonclassic lipoid CAH is a recently recognized disorder caused by mutations in the steroidogenic acute regulatory protein (StAR) that retain partial function.
  
  
  OBJECTIVE
  We describe two siblings with hormonal findings suggesting nonclassic lipoid CAH, who had a P450scc mutation that retains partial function.
  
  
  METHODS
  A 46,XY male presented with underdeveloped genitalia and partial adrenal insufficiency; his 46,XX sister presented with adrenal insufficiency. Hormonal studies suggested nonclassic lipoid CAH. Sequencing of the StAR gene was normal, but compound heterozygous mutations were found in the CYP11A1 gene. Mutations were recreated in the F2 plasmid expressing a fusion protein of the cholesterol side-chain cleavage system. P450scc activity was measured as Vmax/Km for pregnenolone production in transfected COS-1 cells.
  
  
  RESULTS
  The patients were compound heterozygous for the previously described frameshift mutation 835delA and the novel missense mutation A269V. When expressed in the P450scc moiety of F2, the A269V mutant retained 11% activity of the wild-type F2 protein.
  
  
  CONCLUSIONS
  There is a broad clinical spectrum of P450scc deficiency. Partial loss-of-function CYP11A1 mutation can present with a hormonal phenotype indistinguishable from nonclassic lipoid CAH.
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California 94143-0978, USA.
authors.forename: Taninee
authors.initials: T
authors.lastname: Sahakitrungruang
authors.forename: Meng Kian
authors.initials: MK
authors.lastname: Tee
authors.forename: Piers R
authors.initials: PR
authors.lastname: Blackett
authors.forename: Walter L
authors.initials: WL
authors.lastname: Miller
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics* / Q000378:metabolism; D003456:Cryptorchidism / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation; D005822:Genetic Vectors; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000627:therapeutic use; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense
chemical_list: D000893:Anti-Inflammatory Agents; D004247:DNA; D002786:Cholesterol Side-Chain Cleavage Enzyme; D006854:Hydrocortisone