The role of prokineticins in the pathogenesis of hypogonadotropic hypogonadism

Abstract

The prokineticin system comprises two multifunctional secreted proteins, prokineticin-1 (PROK1) and prokineticin-2 (PROK2), and their cognate G protein-coupled receptors. The prokineticins were originally identified as endogenous regulators of gastrointestinal motility. Currently, these bioactive peptides are involved in a wide spectrum of biological functions, including angiogenesis, neurogenesis, circadian rhythms, nociception, hematopoiesis and immune response. Mice homozygous for null mutations in Prokr2 or Prok2 recapitulate the human phenotype of Kallmann syndrome, exhibiting severe atrophy of the reproductive system and hypoplastic olfactory bulbs. 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.

Fig. 1

Mutations identified in PROK2 and PROKR2. The mutations identified in the heterozygous state are shown in red, the mutations identified in both homozygous and heterozygous states are shown in gray and the mutations identified only in the homozygous state are shown in green. a Peptide sequence of PROK2 (81 amino acids) with the signal peptide (27 amino acids, shown in light blue). Exon 1 includes the signal peptide and the amino acids shown in dark blue. Exon 2 is shown in pink and exon 4 in yellow. Exon 3 is not shown. No mutations have been identified in exon 3. b Schematic representation of PROKR2.