title: Novel DAX1 mutations in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism.
abstract: OBJECTIVE
  Mutations of the DAX1 gene (Dosage-sensitive sex reversal-Adrenal hypoplasia congenita critical region on the X chromosome gene 1), which encodes a novel orphan nuclear receptor, have been identified in patients with X-linked adrenal hypoplasia congenita (AHC) and hypogonadotrophic hypogonadism (HHG). We have investigated two kindreds with AHC and HHG for DAX1 mutations.
  
  
  METHODS
  Two kindreds with five affected males, four carrier females and four unaffected males were investigated. The gonadotrophin deficiency in three of the boys was observed to be partial until mid-puberty. DAX1 mutations in the entire 1413 bp coding region were sought by DNA sequence analysis.
  
  
  RESULTS
  Two DAX1 mutations, situated within exon 1, were detected. These consisted of an insertional mutation at codon 183 that led to a frameshift and a premature Stop at codon 184, and a missense mutation Leu278Pro that involved a highly conserved leucine residue within the proposed ligand binding domain. Co-segregation of these mutations with the disease in each family, and their absence from 107 alleles in 73 (39 males and 34 females) unrelated control individuals, was demonstrated by allele specific oligonucleotide hybridization (ASO) analysis for the insertional mutation, and by Ban I restriction endonuclease analysis for the missense mutation.
  
  
  CONCLUSIONS
  Two novel DAX1 mutations have been detected in two families with adrenal hypoplasia and hypogonadotrophic hypogonadism. The finding of partial gonadotrophin deficiency in the affected males from these families is notable and an early recognition of such a possibility in a patient, which may be facilitated by DAX1 mutational analysis, may help to prevent the sequelae of delayed androgen replacement therapy.
authors.affiliation: MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Bassett
authors.forename: D J
authors.initials: DJ
authors.lastname: O'Halloran
authors.forename: G R
authors.initials: GR
authors.lastname: Williams
authors.forename: C G
authors.initials: CG
authors.lastname: Beardwell
authors.forename: S M
authors.initials: SM
authors.lastname: Shalet
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000097:blood / Q000151:congenital* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D016368:Frameshift Mutation; D007987:Gonadotropin-Releasing Hormone; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000151:congenital* / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone