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). [5] [6] [7] The NR0B1 gene is located on the short (p) arm of the X chromosome between bands Xp21.3 and Xp21.2, 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. [8] The encoded protein acts as a dominant-negative regulator of transcription of other nuclear receptors including steroidogenic factor 1. [9] 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. [5]
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 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.
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, [10] 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:
Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.
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.
The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.
Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.
(See also: List of proteins in the human body)
The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.
The liver receptor homolog-1 (LRH-1) also known as totipotency pioneer factor NR5A2 is a protein that in humans is encoded by the NR5A2 gene. LRH-1 is a member of the nuclear receptor family of intracellular transcription factors.
Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the GNRHR gene.
The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.
Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.
Prokineticin receptor 2 (PKR2), is a dimeric G protein-coupled receptor encoded by the PROKR2 gene in humans.
COP9 signalosome complex subunit 2 is a protein that in humans is encoded by the COPS2 gene. It encodes a subunit of the COP9 signalosome.
Hyperglycerolemia, also known as glycerol kinase deficiency (GKD), is a genetic disorder where the enzyme glycerol kinase is deficient resulting in a build-up of glycerol in the body. Glycerol kinase is responsible for synthesizing triglycerides and glycerophospholipids in the body. Excess amounts of glycerol can be found in the blood and/ or urine. Hyperglycerolmia occurs more frequently in males. Hyperglycerolemia is listed as a "rare disease", which means it affects less than 200,000 people in the US population, or less than about 1 in 1500 people.
Hypergonadotropic hypogonadism (HH), also known as primary or peripheral/gonadal hypogonadism or primary gonadal failure, is a condition which is characterized by hypogonadism which is due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid production. As compensation and the lack of negative feedback, gonadotropin levels are elevated. Individuals with HH have an intact and functioning hypothalamus and pituitary glands so they are still able to produce FSH and LH. HH may present as either congenital or acquired, but the majority of cases are of the former nature. HH can be treated with hormone replacement therapy.
An inborn error of steroid metabolism is an inborn error of metabolism due to defects in steroid metabolism.
Leydig cell hypoplasia (LCH), also known as Leydig cell agenesis, is a rare autosomal recessive genetic and endocrine syndrome affecting an estimated 1 in 1,000,000 genetic males. It is characterized by an inability of the body to respond to luteinizing hormone (LH), a gonadotropin which is normally responsible for signaling Leydig cells of the testicles to produce testosterone and other androgen sex hormones. The condition manifests itself as pseudohermaphroditism, hypergonadotropic hypogonadism, reduced or absent puberty, and infertility.
Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.
About 10–15% of human couples are infertile, unable to conceive. In approximately in half of these cases, the underlying cause is related to the male. The underlying causative factors in the male infertility can be attributed to environmental toxins, systemic disorders such as, hypothalamic–pituitary disease, testicular cancers and germ-cell aplasia. Genetic factors including aneuploidies and single-gene mutations are also contributed to the male infertility. Patients with nonobstructive azoospermia or oligozoospermia show microdeletions in the long arm of the Y chromosome and/or chromosomal abnormalities, each with the respective frequency of 9.7% and 13%. A large percentage of human male infertility is estimated to be caused by mutations in genes involved in primary or secondary spermatogenesis and sperm quality and function. Single-gene defects are the focus of most research carried out in this field.
To date, at least 25 different genes have been implicated in causing gonadotropin-releasing hormone (GnRH) deficiency conditions such as Kallmann syndrome (KS) or other forms of congenital hypogonadotropic hypogonadism (CHH) through a disruption in the production or activity of GnRH. These genes involved cover all forms of inheritance, and no one gene defect has been shown to be common to all cases, which makes genetic testing and inheritance prediction difficult.
Melanocortin 2 receptor accessory protein is a transmembrane accessory protein that in humans is encoded by the MRAP gene located in chromosome 21q22.11. Alternate splicing of the MRAP mRNA generates two functionally isoforms MRAP-α and MRAP-β.
