Indeed, the evidence from several naturally inactivating mutations in the PROK2 and PROKR2 genes in patients with Kallmann syndrome and normosmic hypogonadotropic hypogonadism also indicate the essential role of PROK2 in olfactory bulb morphogenesis and GnRH secretion in humans.
Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis.
Prok2 and prokr2 gene knockout mice both have agenesis or hypoplasia of the olfactory bulbs, associated with hypogonadotropic hypogonadism linked to abnormal GnRH neuron migration.
In addition, Prok2(-/-) mice with olfactory bulb defects exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism.