|, AHC, AHCH, AHX, DAX-1, DAX1, DSS, GTD, HHG, NROB1, SRXY2, nuclear receptor subfamily 0 group B member 1|
|RNA expression pattern|
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DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1) is a nuclear receptor protein that in humans is encoded by the NR0B1 gene (nuclear receptor subfamily 0, group B, member 1). The NR0B1 gene is located on the short (p) arm of the X chromosome between positions 21.3 and 21.2, from base pair 30,082,120 to base pair 30,087,136.
This gene encodes a protein that lacks the normal DNA-binding domain contained in other nuclear receptors. The encoded protein acts as a dominant-negative regulator of transcription of other nuclear receptors including steroidogenic factor 1. This protein also functions as an anti-testis gene by acting antagonistically to SRY. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.
DAX1 plays an important role in the normal development of several hormone-producing tissues. These tissues include the adrenal glands above each kidney, the pituitary gland and hypothalamus, which are located in the brain, and the male and female reproductive structures (the testes and ovaries). DAX1 controls the activity of certain genes in the cells that form these tissues during embryonic development. Proteins that control the activity of other genes are known as transcription factors. DAX1 also plays a role in regulating hormone production in these tissues after they have been formed.
Role in disease
X-linked adrenal hypoplasia congenita is caused by mutations in the NR0B1 gene. More than 90 NR0B1 mutations that cause X-linked adrenal hypoplasia congenita have been identified. Many of these mutations delete all or part of the NR0B1 gene, preventing the production of DAX1 protein. Some mutations cause the production of an abnormally short protein. Other mutations cause a change in one of the building blocks (amino acids) of DAX1. These mutations are thought to result in a misshapen, nonfunctional protein. Loss of DAX1 function leads to adrenal insufficiency and hypogonadotropic hypogonadism, which are the main characteristics of this disorder.
Duplication of genetic material on the X chromosome in the region that contains the NR0B1 gene can cause a condition called dosage-sensitive sex reversal. The extra copy of the NR0B1 gene prevents the formation of male reproductive tissues. People who have this duplication usually appear to be female, but are genetically male with both an X and a Y chromosome.
In some cases, genetic material is deleted from the X chromosome in a region that contains several genes, including NR0B1. This deletion results in a condition called adrenal hypoplasia congenita with complex glycerol kinase deficiency. In addition to the signs and symptoms of adrenal hypoplasia congenita, individuals with this condition may have elevated levels of lipids in their blood and urine and may have problems regulating blood sugar levels. In rare cases, the amount of genetic material deleted is even more extensive and affected individuals also have Duchenne muscular dystrophy.
DAX1 has been shown to interact with:
- "Entrez Gene: NR0B1 nuclear receptor subfamily 0, group B, member 1".
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- Muscatelli F, Strom TM, Walker AP, Zanaria E, Récan D, Meindl A, Bardoni B, Guioli S, Zehetner G, Rabl W (Dec 1994). "Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism". Nature 372 (6507): 672–6. doi:10.1038/372672a0. PMID 7990958.
- Guo W, Burris TP, McCabe ER (Oct 1995). "Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis". Biochemical and Molecular Medicine 56 (1): 8–13. doi:10.1006/bmme.1995.1049. PMID 8593542.
- Yanase T, Takayanagi R, Oba K, Nishi Y, Ohe K, Nawata H (Feb 1996). "New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism". The Journal of Clinical Endocrinology and Metabolism 81 (2): 530–5. doi:10.1210/jc.81.2.530. PMID 8636263.
- Guo W, Burris TP, Zhang YH, Huang BL, Mason J, Copeland KC, Kupfer SR, Pagon RA, McCabe ER (Jul 1996). "Genomic sequence of the DAX1 gene: an orphan nuclear receptor responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism". The Journal of Clinical Endocrinology and Metabolism 81 (7): 2481–6. doi:10.1210/jc.81.7.2481. PMID 8675564.
- Nakae J, Tajima T, Kusuda S, Kohda N, Okabe T, Shinohara N, Kato M, Murashita M, Mukai T, Imanaka K, Fujieda K (Oct 1996). "Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita". The Journal of Clinical Endocrinology and Metabolism 81 (10): 3680–5. doi:10.1210/jc.81.10.3680. PMID 8855822.
- Schwartz M, Blichfeldt S, Müller J (Jan 1997). "X-linked adrenal hypoplasia in a large Greenlandic family. Detection of a missense mutation (N4401) in the DAX-1 gene; implication for genetic counselling and carrier diagnosis". Human Genetics 99 (1): 83–7. doi:10.1007/s004390050316. PMID 9003500.
- Takahashi T, Shoji Y, Shoji Y, Haraguchi N, Takahashi I, Takada G (Mar 1997). "Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenita". The Journal of Pediatrics 130 (3): 485–8. doi:10.1016/S0022-3476(97)70217-8. PMID 9063431.
- Nakae J, Abe S, Tajima T, Shinohara N, Murashita M, Igarashi Y, Kusuda S, Suzuki J, Fujieda K (Nov 1997). "Three novel mutations and a de novo deletion mutation of the DAX-1 gene in patients with X-linked adrenal hypoplasia congenita". The Journal of Clinical Endocrinology and Metabolism 82 (11): 3835–41. doi:10.1210/jc.82.11.3835. PMID 9360549.
- Zazopoulos E, Lalli E, Stocco DM, Sassone-Corsi P (Nov 1997). "DNA binding and transcriptional repression by DAX-1 blocks steroidogenesis". Nature 390 (6657): 311–5. doi:10.1038/36899. PMID 9384387.
- GeneReviews/NCBI/NIH/UW entry on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
- OMIM entries on 46,XY Disorder of Sex Development and 46,XY Complete Gonadal Dysgenesis
- GeneReviews/NIH/NCBI/UW entry on X-Linked Adrenal Hypoplasia Congenita including Complex Glycerol Kinase Deficiency
- GeneCard for NR0B1