title: The novel mutation p.Trp147Arg of the steroidogenic acute regulatory protein causes classic lipoid congenital adrenal hyperplasia with adrenal insufficiency and 46,XY disorder of sex development.
abstract: BACKGROUND
  The steroidogenic acute regulatory protein (StAR) is essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause lipoid congenital adrenal hyperplasia.
  
  
  OBJECTIVE
  To identify causative mutations in a patient presenting with adrenal failure during early infancy. The objective was to study the functional and structural consequences of the novel StAR mutation p.Trp147Arg in a Turkish patient detected in compound heterozygosity with the p.Glu169Lys mutation.
  
  
  RESULTS
  Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.Trp147Arg mutant. The previously described p.Glu169Lys mutant led to significantly lower cholesterol conversion than wild-type StAR protein. As derived from three-dimensional protein modeling, the residue W147 is stabilizing the C-terminal helix in a closed conformation hereby acting as gatekeeper of the ligand cavity of StAR.
  
  
  CONCLUSIONS
  The novel mutation p.Trp147Arg causes primary adrenal insufficiency and complete sex reversal in the 46,XY patient. Clinical disease, in vitro studies and three-dimensional protein modeling of the mutation p.Trp147Arg underscore the relevance of this highly conserved residue for StAR protein function.
authors.affiliation: Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, Cukurova University, Balcali/Adana, Turkey.
authors.forename: Bilgin
authors.initials: B
authors.lastname: Yüksel
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Kulle
authors.forename: Fatih
authors.initials: F
authors.lastname: Gürbüz
authors.forename: Maik
authors.initials: M
authors.lastname: Welzel
authors.forename: Damla
authors.initials: D
authors.lastname: Kotan
authors.forename: Eda
authors.initials: E
authors.lastname: Mengen
authors.forename: Paul-Martin
authors.initials: PM
authors.lastname: Holterhus
authors.forename: Ali Kemal
authors.initials: AK
authors.lastname: Topaloğlu
authors.forename: Joachim
authors.initials: J
authors.lastname: Grötzinger
authors.forename: Felix G
authors.initials: FG
authors.lastname: Riepe
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics / Q000378:metabolism; D000309:Adrenal Insufficiency / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D000325:Adrenodoxin / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics / Q000378:metabolism; D005287:Ferredoxin-NADP Reductase / Q000235:genetics / Q000378:metabolism; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013329:Structure-Activity Relationship; D014421:Turkey; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D000325:Adrenodoxin; D002784:Cholesterol; D005287:Ferredoxin-NADP Reductase