title: Four Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by DAX-1 gene mutations: mutant DAX-1 failed to repress steroidogenic acute regulatory protein (StAR) and luteinizing hormone beta-subunit gene promoter activity.
abstract: Mutations of DSS (dosage sensitive sex reversal)-AHC critical region on the X chromosome, gene 1 DAX-1(NROB1)] results in X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG). Here we report four Japanese patients with AHC and HHG caused by the mutations of the DAX-1 gene. All patients manifested adrenal crisis at early childhood. Three patients did not show any pubertal sign and were diagnosed as having HHG. One patient manifested spontaneous pubertal development at 17 years of age. Nevertheless, his puberty did not develop further and his gonadotropin and testosterone levels decreased thereafter. Therefore, he was also diagnosed as having HHG. We performed testicular biopsy in another patient with HHG. Histological examination demonstrated Sertoli cell hypoplasia and no sperm formation in the seminiferous tubules. Molecular analysis demonstrated two novel point mutations (V269D and L278R) in two patients. Transient transfection assays showed that all these mutations (V269D, L271X, L278R, and Q395X) abolished the repression activity to both StAR and LHbeta gene promoter activation. In conclusion, we reported patients with AHC and HHG caused by the loss of function mutations of the DAX-1 gene.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okuhara
authors.forename: Shuji
authors.initials: S
authors.lastname: Abe
authors.forename: Takuma
authors.initials: T
authors.lastname: Kondo
authors.forename: Keinosuke
authors.initials: K
authors.lastname: Fujita
authors.forename: Noya
authors.initials: N
authors.lastname: Koda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujieda
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
mesh_terms: D000293:Adolescent; D000303:Adrenal Cortex Diseases / Q000150:complications / Q000151:congenital / Q000235:genetics*; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D057137:DAX-1 Orphan Nuclear Receptor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D015536:Down-Regulation / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000150:complications / Q000235:genetics*; D007564:Japan; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics*; D008297:Male; D051379:Mice; D050505:Mutant Proteins / Q000502:physiology; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D037101:Luteinizing Hormone, beta Subunit; D050505:Mutant Proteins; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; D010750:Phosphoproteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000098682:Steroidogenic Acute Regulatory Protein