Disease relevance of NR0B1

• Mutations in NR0B1 cause the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC), and associated hypogonadotropic hypogonadism (HH) [1].
• Mutations in the orphan nuclear receptor DAX1 (NR0B1) cause X-linked adrenal hypoplasia congenital (AHC), a disorder characterized by primary adrenal failure, hypogonadotropic hypogonadism. and azoospermia [2].
• OBJECTIVE: Our objective was to investigate the prevalence of DAX1 and SF1 mutations in children and adults with primary adrenal failure of unknown etiology (i.e. not caused by congenital adrenal hyperplasia, adrenoleukodystrophy, or autoimmune disease) [3].
• RESULTS: Eleven clinically non-functioning adenomas expressed DAX-1, 10 of which also expressed Ad4BP/SF-1 [4].
• Expression of an orphan nuclear receptor DAX-1 in human pituitary adenomas [4].

Psychiatry related information on NR0B1

• We report on deletion mapping and X inactivation analysis of a gene for X linked non-specific mental retardation (MRX) at Xp21.3-Xp22.11, on the basis of molecular studies in two families with Xp microdeletions involving the DAX-1 gene [5].
• The authors conclude that the AHC grant program has been successful in generating external research funds (primarily National Institutes of Health) and publications; stimulating risk-taking; and developing interdisciplinary and intercollegiate collaboration [6].
• A DSS can use these guideline statements in multiple ways, including: (1) as inputs for determining preferred alternatives in decision-making, and (2) as a way to provide targeted commentaries in the clinical information system [7].

High impact information on NR0B1

• Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene [8].
• The identification of male individuals deleted for DSS suggests that this locus is not required for testis differentiation [9].
• We have named this locus DSS (Dosage Sensitive Sex reversal) and localized it to a 160 kilobase region of chromosome Xp21, adjacent to the adrenal hypoplasia congenita locus [9].
• Here we show that DAX-1 binds DNA and acts as a powerful transcriptional repressor of StAR gene expression, leading to a drastic decrease in steroid production [10].
• DAX-1 is an unusual member of the nuclear-receptor superfamily of transcription factors which contains no canonical zinc-finger or any other known DNA-binding motif [10].

Chemical compound and disease context of NR0B1

• In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 +/- 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 +/- 4%) [11].
• Molecular studies of the glycerol kinase (GK) and DAX1 genes were performed on four cases of "persistent hypertriglyceridemia" found in an Italian population and on two pediatric cases with high serum glycerol concentration [12].
• Cortisol-producing adenomas showed intermediate DAX-1 expression (n = 8; 92 +/- 16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%) [13].
• We found low or absent DAX-1 expression in aldosterone-producing adenomas (n = 11: 35 +/- 11%; normal adrenals: 100 +/- 17%) and in aldosterone-producing adrenocortical carcinomas (n = 2: 24 and 36%) [13].
• In this Eastern Cooperative Oncology Group (ECOG) phase II study, dibromodulcitol (DBD) and a combination of actinomycin D, hydroxyurea, and cyclophosphamide (AHC) were compared with methyl-CCNU, the current ECOG standard, in patients who had received no prior chemotherapy for disseminated malignant melanoma [14].

Biological context of NR0B1

• DAX-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita-critical region on the X chromosome gene 1; NR0B1) is an orphan nuclear receptor that plays an important role in the development and functioning of the adrenal gland and hypothalamic-pituitary gonadal axis [15].
• Over-expression of NR0B1 results in sex reversal in mice and duplication of the 160kb DSS locus in human patients results in a sex-reversed phenotype (XY females) [1].
• We show that DAX-1 potently inhibits ligand-dependent transcriptional activation as well as the interaction between the N- and C-terminal activation domains of AR [16].
• Identification of a novel missense mutation that is as damaging to DAX-1 repressor function as a nonsense mutation [17].
• Transient transfection assays demonstrated that both mutations resulted in a severe loss of DAX-1 repressor activity [17].

Anatomical context of NR0B1

• Immunohistochemistry and H-scoring showed that DAX-1 was ubiquitously present in epithelial and stromal cells of both tissues [18].
• In the ovarian follicle and corpora lutea, immunoreactive DAX-1 protein was detected predominantly in granulosa cells, whereas COUP-TFII was identified in thecal cells [19].
• Like DAX-1, SF-1 expression has been shown to be essential for the development of the adrenal cortex [20].
• Both DAX-1 and SF-1 are expressed in similar tissues including the adrenal cortex, gonads, hypothalamus, and the pituitary gland [20].
• Here, we report that murine Dax1 is a unique marker in early embryonic development, distinguishing the extraembryonic (proximal) endoderm from the remainder of the developing embryo [21].

Associations of NR0B1 with chemical compounds

• These results implicate novel inhibitory mechanisms of DAX-1 action with particular relevance for the modulation of androgen-dependent gene transcription in the male reproductive system [16].
• DAX-1 functions as a global negative regulator of steroid hormone production [22].
• The expression of DAX-1 protein was slightly inhibited by 10(-6) m oestradiol (E2) at 6 h but enhanced by 10(-6) m dihydrotestosterone (DHT) at 48 h [23].
• The DAX-1 product acts as a dominant negative regulator of transcription mediated by the retinoic acid receptor [24].
• We provide in vitro and in vivo evidence that DAX-1 binds to DNA hairpin structures [10].

Physical interactions of NR0B1

• We provide evidence for direct interactions of the two receptors that involve the N-terminal repeat domain of DAX-1 and the C-terminal ligand-binding and activation domain of AR [16].
• A luciferase assay also indicated that these two cofactors enhanced Ad4BP/SF-1 transactivation.Dosage-sensitive sex reversal (DAX-1) interacts with and thus inhibits Ad4BP/SF-1 transactivation [25].
• Naturally occurring mutants of the DAX-1 gene fail to interact with Alien and have lost silencing function [26].
• We have discovered that the orphan receptor DAX-1 (NROB1) interacts with the estrogen receptors ERalpha and ERbeta [27].

Enzymatic interactions of NR0B1

• The DAX-1 gene was entirely deleted in a 3rd patient as well as in a 4th with the additional feature of glycerol kinase deficiency [28].

Regulatory relationships of NR0B1

• CONCLUSIONS: The results shown here indicate that DAX-1 is expressed in the majority of human pituitary adenomas of gonadotrophic origin in parallel with Adrenal-4-binding protein/steroidogenic factor-1 [4].
• WT1 and DAX-1 inhibit aromatase P450 expression in human endometrial and endometriotic stromal cells [18].
• Furthermore, Northern experiments demonstrate that Alien is expressed in the adrenal gland and testis in tissues where DAX-1 is specifically expressed [26].
• The orphan nuclear receptor DAX1 is up-regulated by the EWS/FLI1 oncoprotein and is highly expressed in Ewing tumors [29].

Other interactions of NR0B1

• Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1 [16].
• Recent studies have demonstrated that DAX-1 and COUP-TFII negatively regulate adrenal 4 binding protein (Ad4BP)/steroidogenic factor-1 (SF-1)-dependent transcription of steroidogenic enzymes in experimental animals [19].
• No significant correlations were detected between DAX-1 immunoreactivity and amounts of aromatase mRNA [22].
• There was a statistically significant positive correlation between DAX-1 and ERalpha (P = 0.006) and ERbeta LI (P < 0.001) [22].
• These findings suggest that DAX-1 may inhibit the proliferation and progression of endometrial carcinoma through inhibition of estrogenic actions, possibly by interacting with ER present in carcinoma cells, rather than regulating in situ steroidogenesis [22].

Analytical, diagnostic and therapeutic context of NR0B1

• We confirmed the presence of an alternatively spliced form of NR0B1, which we will refer to as NR0B1A, by reverse transcriptase-polymerase chain reaction (RT-PCR), and will refer to the deduced protein isoform as DAX1A [1].
• Evaluation for DAX1, SF1 mutations using Southern blotting, PCR, PCR amplification, coding sequences, and splice site analyses have not detected any genetic abnormalities [30].
• We used Northern blot analysis and reverse transcription PCR to demonstrate that DAX-1 was expressed in the hypothalamus and the pituitary, and to confirm its expression in adrenal cortex and gonads [31].
• METHODS: In this study we evaluated, by immunohistochemistry and Western blot analysis, the presence and distribution of DAX-1 in benign breast disease (BBD), in situ carcinoma (CIS), and ductal and lobular breast carcinomas [32].
• The facial expression of SOX-9 seemed to be higher in the acne-prone male patients, while DAX-1 was stronger in subjects without acne, although both were statistically insignificant [23].

References