2.1. 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.

2.2. 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.