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	Koji Okuhara, Shuji Abe, Takuma Kondo, Keinosuke Fujita, Noya Koda, Hiroshi Mochizuki, Kenji Fujieda, Toshihiro Tajima
Journal	Endocrine journal (Endocr J) Vol. 55 Issue 1 Pg. 97-103 (Mar 2008) ISSN: 1348-4540 [Electronic] Japan
PMID	18202527 (Publication Type: Case Reports, Journal Article)
Chemical References	DAX-1 Orphan Nuclear Receptor DNA-Binding Proteins Luteinizing Hormone, beta Subunit Mutant Proteins NR0B1 protein, human Nr0b1 protein, mouse Phosphoproteins Receptors, Retinoic Acid Repressor Proteins steroidogenic acute regulatory protein
Topics	Adolescent Adrenal Cortex Diseases (complications, congenital, genetics) Adult Animals Base Sequence Cells, Cultured DAX-1 Orphan Nuclear Receptor DNA Mutational Analysis DNA-Binding Proteins (genetics, physiology) Down-Regulation (genetics) Humans Hypogonadism (complications, genetics) Japan Luteinizing Hormone, beta Subunit (genetics) Male Mice Mutant Proteins (physiology) Mutation Phosphoproteins (genetics) Promoter Regions, Genetic Receptors, Retinoic Acid (genetics, physiology) Repressor Proteins (genetics, physiology) Transfection

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