title: Characterization of novel StAR (steroidogenic acute regulatory protein) mutations causing non-classic lipoid adrenal hyperplasia.
abstract: BACKGROUND
  Steroidogenic acute regulatory protein (StAR) is crucial for transport of cholesterol to mitochondria where biosynthesis of steroids is initiated. Loss of StAR function causes lipoid congenital adrenal hyperplasia (LCAH).
  
  
  OBJECTIVE
  StAR gene mutations causing partial loss of function manifest atypical and may be mistaken as familial glucocorticoid deficiency. Only a few mutations have been reported.
  
  
  METHODS
  To report clinical, biochemical, genetic, protein structure and functional data on two novel StAR mutations, and to compare them with published literature.
  
  
  METHODS
  Collaboration between the University Children's Hospital Bern, Switzerland, and the CIBERER, Hospital Vall d'Hebron, Autonomous University, Barcelona, Spain.
  
  
  METHODS
  Two subjects of a non-consanguineous Caucasian family were studied. The 46,XX phenotypic normal female was diagnosed with adrenal insufficiency at the age of 10 months, had normal pubertal development and still has no signs of hypergonodatropic hypogonadism at 32 years of age. Her 46,XY brother was born with normal male external genitalia and was diagnosed with adrenal insufficiency at 14 months. Puberty was normal and no signs of hypergonadotropic hypogonadism are present at 29 years of age.
  
  
  RESULTS
  StAR gene analysis revealed two novel compound heterozygote mutations T44HfsX3 and G221S. T44HfsX3 is a loss-of-function StAR mutation. G221S retains partial activity (∼30%) and is therefore responsible for a milder, non-classic phenotype. G221S is located in the cholesterol binding pocket and seems to alter binding/release of cholesterol.
  
  
  CONCLUSIONS
  StAR mutations located in the cholesterol binding pocket (V187M, R188C, R192C, G221D/S) seem to cause non-classic lipoid CAH. Accuracy of genotype-phenotype prediction by in vitro testing may vary with the assays employed.
authors.affiliation: Pediatric Endocrinology and Diabetology, University Children's Hospital Bern, Bern, Switzerland. christa.flueck@dkf.unibe.ch
authors.forename: Christa E
authors.initials: CE
authors.lastname: Flück
authors.forename: Amit V
authors.initials: AV
authors.lastname: Pandey
authors.forename: Bernhard
authors.initials: B
authors.lastname: Dick
authors.forename: Núria
authors.initials: N
authors.lastname: Camats
authors.forename: Mónica
authors.initials: M
authors.lastname: Fernández-Cancio
authors.forename: María
authors.initials: M
authors.lastname: Clemente
authors.forename: Miquel
authors.initials: M
authors.lastname: Gussinyé
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrascosa
authors.forename: Primus E
authors.initials: PE
authors.lastname: Mullis
authors.forename: Laura
authors.initials: L
authors.lastname: Audi
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002784:Cholesterol / Q000378:metabolism; D058490:Disorder of Sex Development, 46,XY / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D011487:Protein Conformation; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics; D035781:Siblings; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D005938:Glucocorticoids; D050505:Mutant Proteins; D010750:Phosphoproteins; D044103:Receptor, Melanocortin, Type 2; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol