title: Progressive onset of adrenal insufficiency and hypogonadism of pituitary origin caused by a complex genetic rearrangement within DAX-1.
abstract: DAX-1 [dosage-sensitive sex reversal, adrenal hypoplasia congenital (AHC) critical region on the X chromosome, gene 1] is a transcription factor expressed in the adrenal gland and at all levels of the gonadotrope axis. Inactivating mutations of DAX1 result in the X-linked form of AHC with associated hypogonadotropic hypogonadism. AHC usually reveals itself as adrenal failure in early infancy, although a wide range of phenotypic expression has been reported. We describe a patient who was diagnosed with adrenal failure at 6 wk of age, but who experienced recovery of adrenal function of several months' duration later in infancy. He subsequently failed to undergo puberty because of hypogonadotropic hypogonadism of pituitary origin, and he was also diagnosed with schizophrenia in early adulthood. Molecular genetic analyses revealed a complex rearrangement in DAX1, including a 2.2-kb deletion spanning the entire second exon and a small 27-bp insertion. The putative protein encoded by this mutated gene is 429 amino acids long. The initial 389 residues probably correspond to the wild-type DAX-1 sequence, whereas the last 40 amino acids are presumably completely unrelated, being transcribed from the intronic sequence adjacent to exon 1. In vitro functional analyses confirm the absence of repressor activity exerted by such mutant protein. These studies expand the genotypic and phenotypic spectrum of DAX-1 insufficiency in humans.
authors.affiliation: Division of Endocrinology and Diabetology, University Hospital, 1011 Lausanne, Switzerland.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvi
authors.forename: Fulgencio
authors.initials: F
authors.lastname: Gomez
authors.forename: Muriel
authors.initials: M
authors.lastname: Fiaux
authors.forename: Daniel
authors.initials: D
authors.lastname: Schorderet
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Rolf C
authors.initials: RC
authors.lastname: Gaillard
authors.forename: François P
authors.initials: FP
authors.lastname: Pralong
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D057137:DAX-1 Orphan Nuclear Receptor; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D015321:Gene Rearrangement; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007018:Hypopituitarism / Q000235:genetics*; D008297:Male; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D017931:DNA Primers; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors