title: Unique dominant negative mutation in the N-terminal mitochondrial targeting sequence of StAR, causing a variant form of congenital lipoid adrenal hyperplasia.
abstract: BACKGROUND
  Steroid acute regulatory (StAR) protein is a mitochondria-targeted protein that is part of the transduceosome complex crucial for transport of cholesterol to mitochondria. Recessive mutations cause classic and nonclassic congenital lipoid adrenal hyperplasia.
  
  
  OBJECTIVE
  The aim of this study was to report the clinical, hormonal, genetic, and functional data of a novel heterozygous mutation in the StAR gene found in a 46,XY patient with ambiguous genitalia and neonatal severe steroidogenic deficiency.
  
  
  METHODS
  Undetectable serum steroids with high ACTH and plasma renin activity but normal acute GnRH response were found in infancy. After gonadectomy (at 3 yr of age), serum LH and testosterone were undetectable, whereas FSH was normal but increased slowly afterward. Estrogen replacement therapy, started at 10.2 yr of age, suppressed gonadotropins (for 2 yr). However, after 1 month off estrogens, the patient showed castrated levels. At 11.9 yr old, after fludrocortisone withdrawal because of hypertension, plasma renin activity and aldosterone remained normal, suggesting mineralocorticoid recovery by a StAR-independent mechanism.
  
  
  RESULTS
  We found a de novo heterozygous IVS-2A>G StAR mutation and the reported heterozygous p.G146A SF1 polymorphism with normal CYP11A1, FDXR, FDX1, VDAC1, and TSPO genes. The mutant StAR transcript lacked exon 2, resulting in the in-frame loss of amino acids 22 to 59 in the N-terminal mitochondrial targeting signal. In vitro, the mutant protein exhibited reduced StAR activity in a dominant-negative manner and almost no mitochondria localization.
  
  
  CONCLUSIONS
  A misfolded p.G22_L59del StAR might interfere with wild-type StAR activity by blocking the transduceosome complex, causing an autosomal dominant form of StAR deficiency, explaining the clinical phenotype. We speculated that estrogen might have modulated mineralocorticoid function and pubertal maturation in a human natural model lacking endogenous steroid production.
authors.affiliation: Endocrine Service, Hospital de Pediatria Garrahan, Buenos Aires C1245AAM, Argentina.
authors.forename: María Sonia
authors.initials: MS
authors.lastname: Baquedano
authors.forename: Gabriela
authors.initials: G
authors.lastname: Guercio
authors.forename: Roxana
authors.initials: R
authors.lastname: Marino
authors.forename: Esperanza
authors.initials: E
authors.lastname: Berensztein
authors.forename: Mariana
authors.initials: M
authors.lastname: Costanzo
authors.forename: Marcela
authors.initials: M
authors.lastname: Bailez
authors.forename: Elisa
authors.initials: E
authors.lastname: Vaiani
authors.forename: Mercedes
authors.initials: M
authors.lastname: Maceiras
authors.forename: Pablo
authors.initials: P
authors.lastname: Ramirez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Chaler
authors.forename: Marco A
authors.initials: MA
authors.lastname: Rivarola
authors.forename: Alicia
authors.initials: A
authors.lastname: Belgorosky
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D012734:Disorders of Sex Development / Q000235:genetics; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D020125:Mutation, Missense / Q000502:physiology; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D021382:Protein Sorting Signals / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D021382:Protein Sorting Signals; D000098682:Steroidogenic Acute Regulatory Protein