DAX1
Encyclopedia
DAX1 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.
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 gland
s), 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.
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
.
with:
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
protein that in humans is encoded by the NR0B1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(nuclear receptor subfamily 0, group B, member 1). The NR0B1 gene is located on the short (p) arm of the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
between positions 21.3 and 21.2, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
30,082,120 to base pair 30,087,136.
Function
This gene encodes a protein that lacks the normal DNA-binding domainDNA-binding domain
A DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
contained in other nuclear receptors. The encoded protein acts as a dominant-negative regulator of transcription of other nuclear receptors including steroidogenic factor 1
Steroidogenic factor 1
The steroidogenic factor 1 protein controls sexual development in the embryo and at puberty.SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene .- Function :SF-1 is a critical regulator of reproduction, regulating the transcription...
. This protein also functions as an anti-testis gene by acting antagonistically to SRY
SRY
SRY is a sex-determining gene on the Y chromosome in the therians .This intronless gene encodes a transcription factor that is a member of the SOX gene family of DNA-binding proteins...
. 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 gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s), the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
and hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
which are located in the brain and the male and female reproductive structures (the testes and ovaries
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy: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 congenitaX-linked adrenal hypoplasia congenita
X-linked adrenal hypoplasia congenita is a genetic disorder that mainly affects males. It involves many endocrine tissues in the body, especially the adrenal glands.-Presentation:...
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
Glycerol kinase deficiency
Glycerol Kinase Deficiency is an X-linked recessive enzyme defect that is heterozygous in nature. Three clinically distinct forms of this deficiency have been proposed, namely infantile, juvenile, and adult...
. 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
Duchenne muscular dystrophy
Duchenne muscular dystrophy is a recessive X-linked form of muscular dystrophy, which results in muscle degeneration, difficulty walking, breathing, and death. The incidence is 1 in 3,000 boys. Females and males are affected, though females are rarely affected and are more often carriers...
.
Interactions
DAX1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- COPS2COPS2COP9 signalosome complex subunit 2 is a protein that in humans is encoded by the COPS2 gene.-Interactions:COPS2 has been shown to interact with IRF8, NIF3L1, Thyroid hormone receptor alpha and DAX1.-Further reading:...
, - NRIP1NRIP1Nuclear receptor-interacting protein 1 is a protein that in humans is encoded by the NRIP1 gene.RIP140 has an important role in regulating lipid and glucose metabolism, and regulates gene expression in metabolic tissues including heart, skeletal muscle, and liver.Knockout mice that completely lack...
, - Steroidogenic factor 1Steroidogenic factor 1The steroidogenic factor 1 protein controls sexual development in the embryo and at puberty.SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene .- Function :SF-1 is a critical regulator of reproduction, regulating the transcription...
, and - SREBF1SREBF1Sterol regulatory element-binding transcription factor 1 also known as sterol regulatory element-binding protein 1 is a protein that in humans is encoded by the SREBF1 gene....
.
External Links
- 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