PROKR2 gene

The PROKR2 gene provides instructions for making a protein called prokineticin receptor 2. This receptor interacts with a protein called prokineticin 2 (produced from the PROK2 gene). On the cell surface, prokineticin 2 attaches to the receptor like a key in a lock. When the two proteins are connected, they trigger a series of chemical signals within the cell that regulate various cell functions. Prokineticin 2 and its receptor are produced in many organs and tissues, including the small intestine, certain regions of the brain, and several hormone-producing (endocrine) tissues.

Prokineticin 2 and its receptor play a role in the development of a group of nerve cells that are specialized to process smells (olfactory neurons). These neurons move (migrate) from the developing nose to a structure in the front of the brain called the olfactory bulb, which is critical for the perception of odors. Prokineticin 2 and its receptor are also involved in the migration of nerve cells that produce gonadotropin-releasing hormone (GnRH). GnRH controls the production of several hormones that direct sexual development before birth and during puberty. These hormones are also important for the normal function of the ovaries in women and the testes in men.
Several additional functions of prokineticin 2 and its receptor have been discovered. These proteins help stimulate the movement of food through the intestine and are likely involved in the formation of new blood vessels (angiogenesis). They also play a role in coordinating daily (circadian) rhythms, such as the sleep-wake cycle and regular changes in body temperature. Prokineticin 2 and its receptor are active in a region of the brain called the suprachiasmatic nucleus (SCN), which acts as an internal clock that controls circadian rhythms.

Kallmann syndrome
At least 30 mutations in the PROKR2 gene can cause Kallmann syndrome, a disorder characterized by the combination of hypogonadotropic hypogonadism (a condition affecting the production of hormones that direct sexual development) and an impaired sense of smell. Researchers estimate that mutations in the PROKR2 and PROK2 genes together account for about 9 percent of all cases of Kallmann syndrome.
Most of the PROKR2 gene mutations that cause Kallmann syndrome change single protein building blocks (amino acids) in prokineticin receptor 2. These mutations disrupt the function of the receptor, affecting its ability to trigger chemical signals within cells. A loss of this signaling disrupts the migration and survival of olfactory neurons and GnRH-producing neurons in the developing brain. If olfactory nerve cells do not extend to the olfactory bulb, a person's sense of smell will be impaired or absent. Misplacement or premature loss of GnRH-producing neurons prevents the production of sex hormones, which interferes with normal sexual development and causes puberty to be delayed or absent.
Because the features and severity of Kallmann syndrome vary among individuals, researchers believe that additional genetic and environmental factors may be involved. Some affected individuals have mutations in one of several other genes in addition to PROKR2, and these genetic changes may contribute to the varied features of the condition.

Septo-optic dysplasia
Other disorders A few mutations in the PROKR2 gene have been identified in people with only one of the two major features of Kallmann syndrome (described above): hypogonadotropic hypogonadism or an impaired sense of smell. When hypogonadotropic hypogonadism occurs with a normal ability to smell, it is called normosmic isolated hypogonadotropic hypogonadism (nIHH). An impaired sense of smell without hypogonadotropic hypogonadism is called isolated congenital anosmia (ICA). Like the PROKR2 gene mutations that cause Kallmann syndrome, the mutations associated with these conditions impair the function of prokineticin receptor 2, preventing it from transmitting signals properly. A loss of this signaling can disrupt the migration of GnRH-producing nerve cells or olfactory neurons in the developing brain. It is unclear why some mutations in this gene cause both hypogonadotropic hypogonadism and an impaired sense of smell in people with Kallmann syndrome, and only one of these features in people with nIHH or ICA.

Chromosomal Location
Cytogenetic Location: 20p12.3, which is the short (p) arm of chromosome 20 at position 12.3