title: An amino-terminal DAX1 (NROB1) missense mutation associated with isolated mineralocorticoid deficiency.
abstract: BACKGROUND
  Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes.
  
  
  OBJECTIVE
  The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations.
  
  
  METHODS
  We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1.
  
  
  RESULTS
  The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins.
  
  
  CONCLUSIONS
  We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.
authors.affiliation: Department of Medicine, Northwestern Memorial Hospital, Galter Building 3-150, 251 East Huron Street, Chicago, Illinois 60611, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Verrijn Stuart
authors.forename: G
authors.initials: G
authors.lastname: Ozisik
authors.forename: M A
authors.initials: MA
authors.lastname: de Vroede
authors.forename: J C
authors.initials: JC
authors.lastname: Giltay
authors.forename: R J
authors.initials: RJ
authors.lastname: Sinke
authors.forename: T J
authors.initials: TJ
authors.lastname: Peterson
authors.forename: R M
authors.initials: RM
authors.lastname: Harris
authors.forename: J
authors.initials: J
authors.lastname: Weiss
authors.forename: J L
authors.initials: JL
authors.lastname: Jameson
mesh_terms: D002478:Cells, Cultured; D002648:Child; D003001:Cloning, Molecular; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008901:Mineralocorticoids / Q000172:deficiency*; D008954:Models, Biological; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014162:Transfection
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D008901:Mineralocorticoids; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins