Alternative titles; symbols
HGNC Approved Gene Symbol: PROK2
Cytogenetic location: 3p13 Genomic coordinates (GRCh38) : 3:71,771,655-71,785,148 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p13 | Hypogonadotropic hypogonadism 4 with or without anosmia | 610628 | Autosomal dominant | 3 |
Li et al. (2001) cloned 2 human cDNAs based on the sequence similarity to a frog skin secretion protein, Bv8, and a nontoxic protein of mamba snake venom. They designated the encoded proteins prokineticin-1 (PROK1; 606233) and prokineticin-2. The prokineticin-2 gene encodes a mature protein of 81 amino acids. Northern blot analysis revealed only low expression in small intestine. Prokineticin-2 forms 5 pairs of disulfide bonds. The recombinant proteins potently contract gastrointestinal smooth muscle with an effective concentration, EC50, in the subnanomolar range.
By radiation hybrid analysis, Jilek et al. (2000) mapped the PROK2 gene to chromosome 3p21.1. They mapped the mouse gene to chromosome 6.
Cheng et al. (2002) showed that prokineticin-2 functions as an output molecule from the suprachiasmatic nucleus (SCN) circadian clock. PROK2 mRNA is rhythmically expressed in the SCN, and the phase of PROK2 rhythm is responsive to light entrainment. Molecular and genetic studies revealed that PROK2 is a gene that is controlled by a circadian clock. The receptor for PROK2 (PROKR2; 607123) is abundantly expressed in major target nuclei of the SCN output pathway. Inhibition of nocturnal locomotor activity in rats by intracerebroventricular delivery of recombinant PROK2 during subjective night, when the endogenous PROK2 mRNA level is low, further supports the hypothesis that PROK2 is an output molecule that transmits behavioral circadian rhythm. The high expression of PROKR2 mRNA within the SCN and the positive feedback of PROK2 on its own transcription through activation of PROKR2 suggest that PROK2 may also function locally within the SCN to synchronize output.
Cheng et al. (2002) showed that PROK2 mRNA is expressed in the SCN and among a few other discrete brain areas including the islands of Calleja, medial preoptic area of the hypothalamus, and the shell of the nucleus accumbens. PROK2 mRNA is essentially undetectable in the SCN during the dark phase. PROK1 mRNA is undetectable in the same brain areas. There are 4 conserved E-box elements in the 5-prime flanking sequence of the human PROK2 gene. Cheng et al. (2002) demonstrated that Clock (601851)-Bmal1 (602550) heterodimers can drive PROK2 expression.
Ng et al. (2005) showed that secreted prokineticin-2 functions as a chemoattractant for subventricular zone-derived neuronal progenitors. Within the olfactory bulb, PROK2 may also act as a detachment signal for chain-migrating progenitors arriving from the rostral migratory stream. PROK2 deficiency in mice leads to a marked reduction in olfactory bulb size, loss of normal olfactory bulb architecture, and the accumulation of neuronal progenitors in the rostral migratory stream. Ng et al. (2005) concluded that the findings define a central role for G protein-coupled PROK2 signaling in postnatal and adult olfactory bulb neurogenesis.
Shojaei et al. (2007) showed that implantation of tumor cells in mice resulted in upregulation of Bv8 in CD11b (120980)+Gr1+ myeloid cells. They identified granulocyte colony-stimulating factor (GCSF; 138970) as a major positive regulator of Bv8 expression. Anti-Bv8 antibodies reduced CD11b+Gr1+ cell mobilization elicited by Gcsf. Adenoviral delivery of Bv8 into tumors promoted angiogenesis. Anti-Bv8 antibodies inhibited growth of several tumors in mice and suppressed angiogenesis. Anti-Bv8 treatment also reduced CD11b+Gr1+ cells, both in peripheral blood and in tumors. The effects of anti-Bv8 antibodies were additive to those of anti-Vegf (192240) antibodies or cytotoxic chemotherapy. Thus, Shojaei et al. (2007) concluded that Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumor development and also promotes angiogenesis locally.
Giannini et al. (2009) showed that rodent Pk2 had a role in the perception of inflammatory pain. Induced paw inflammation correlated with the expression levels of Pk2 at inflamed sites and depended mainly on upregulation of Pk2 mRNA in granulocytes. Rat Pk2 purified from peritoneal granulocytes showed high affinity for the prokineticin receptors Pkr1 (PROKR1; 607122) and Pkr2 (PROKR2) and, when injected into rat paw, induced hypersensitivity to noxious stimuli. Mice lacking Pkr1 or Pkr2 developed significantly less inflammation-induced hyperalgesia compared with wildtype. Pretreatment with a nonpeptide Pkr1 antagonist reduced and eventually abolished hypernociception and inflammatory hyperalgesia in a dose-dependent manner.
Kallmann syndrome (see HH4, 610628) combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. By use of a candidate gene strategy in a cohort of 192 patients with Kallmann syndrome, Dode et al. (2006) identified 4 and 10 different point mutations in the PROK2 gene and in its receptor, PROKR2, respectively. The mutations in PROK2 (e.g., 607002.0001-607002.0002) were detected in heterozygous state. The findings demonstrated that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man.
Pitteloud et al. (2007) analyzed the PROK2 gene in 50 probands with normosmic idiopathic hypogonadotropic hypogonadism (see HH4, 610628) and 50 probands with Kallmann syndrome, none of whom had mutations in known causative genes, and found homozygosity for a 1-bp deletion in the PROK2 gene (607002.0003) in 2 brothers with Kallmann syndrome and their sister who had IHH. An unaffected brother was heterozygous for the mutation. Functional studies demonstrated that the truncated protein lacks bioactivity.
Leroy et al. (2008) identified respective homozygous mutations in the PROK2 gene (607002.0003-607002.0004) in 2 of 320 patients with Kallmann syndrome, suggesting that it is a rare cause of the disorder. Leroy et al. (2008) concluded that only biallelic PROK2 mutations result in Kallmann syndrome, and that patients with heterozygous mutations have another pathogenic mutation in a Kallmann-related gene.
In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROK2 and PROKR2 genes and identified 5 and 10 different point mutations, respectively. The 5 mutations in PROK2 were heterozygous in 4 probands (see, e.g., 607002.0004-607002.0006) and homozygous in 1 (607002.0003); 1 of the heterozygous probands (see 607002.0005) also carried a heterozygous mutation in PROKR2 (607123.0007). Four of the probands with a mutation in PROK2 had Kallmann syndrome and 1 reported a normal sense of smell; screening 5 other HH-associated genes revealed no additional mutations. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. Cole et al. (2008) concluded that loss-of-function mutations in PROK2 can cause both Kallmann syndrome and normosmic IHH.
In a patient with anosmic hypogonadotropic hypogonadism (HH16; 614897) who was heterozygous for a missense mutation in the SEMA3A gene (603961), Hanchate et al. (2012) also identified heterozygosity for a frameshift mutation in PROK2. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder.
Pitteloud et al. (2007) generated Prok2 -/- mice which, in addition to olfactory bulb defects, exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in the GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Heterozygous mice did not show an abnormal phenotype.
In a patient with Kallmann syndrome (HH4; 610628), Dode et al. (2006) identified heterozygosity for a 94G-C transversion in exon 1 of the PROK2 gene, resulting in a gly32-to-arg (G32R) substitution. The mutation affected the glycine residue of the N-terminal hexapeptide AVITGA, which is conserved among the prokineticins from mammalian and nonmammalian species and is critical for the bioactivities of these proteins. A sister of the male proband had hypogonadism only. The mutation was not found in 500 alleles from ethnically matched (Caucasian) control individuals.
In affected members of a family with manifestations of Kallmann syndrome-4 (HH4; 610628) in 4 generations, Dode et al. (2006) identified heterozygosity for a 1-nucleotide insertion, a T between nucleotides 234 and 235, in exon 4 of the PROK2 gene, predicted to result in a frameshift at codon 79 with a premature termination at codon 100 (79fsX100). The most recent generation of the family had 2 sisters with full Kallmann syndrome, a brother with hypogonadism only, and 3 unaffected sisters. The mother, maternal grandfather, and great grandfather had anosmia only. The mutation was not found in 500 alleles from ethnically matched (Caucasian) control individuals.
In 2 brothers with anosmic hypogonadotropic hypogonadism and their sister who had normosmic idiopathic hypogonadotropic hypogonadism (HH4; 610628), Pitteloud et al. (2007) identified homozygosity for a 1-bp deletion (163delA) in exon 2 of the PROK2 gene, predicted to result in a premature stop codon at amino acid 55 and a truncated protein of only 27 amino acids. An unaffected brother was heterozygous for the mutation. In vitro analysis of CHO cells expressing PROKR2 (607123) revealed that truncated PROK2 could not activate PROKR2 even at very high concentrations.
Leroy et al. (2008) identified a homozygous 163delA mutation in a Swiss man with hypogonadotropic hypogonadism and complete anosmia.
In a male patient with Kallmann syndrome, Cole et al. (2008) identified homozygosity for the 163delA mutation in the PROK2 gene. The patient did not go through puberty, and luteinizing hormone (LH; see 152780) was undetectable; his sense of smell was below the fifth percentile on olfactory testing, and MRI revealed absence of olfactory bulbs. He also had seizures. Functional analysis in CHO cells demonstrated complete loss of activation of PROKR2 (607123) with the truncated protein (I55fsTer1) even at very high concentrations.
In a patient with sporadic anosmic hypogonadotropic hypogonadism (HH4; 610628), Dode et al. (2006) identified heterozygosity for a c.217C-T transition in exon 2 of the PROK2 gene, resulting in an arg73-to-cys (R73C) substitution at a conserved residue in the cysteine-rich region. The mutation was not found in 500 alleles from ethnically matched controls. Additional features in the patient included marked obesity and a severe sleep disorder, which the authors suggested might be related to the known circadian function of PROK2.
In a Turkish boy, born of consanguineous parents, with Kallmann syndrome, Leroy et al. (2008) identified homozygosity for the R73C substitution in the PROK2 gene. The mutation was not identified in 200 ethnically matched controls. He was referred at the age of 18 because of the absence of spontaneous puberty. He also had anosmia, micropenis, and infantile testes. The olfactory bulbs could not be visualized on MRI. Endocrinologic tests confirmed the presence of hypogonadotropic hypogonadism.
In a female patient with normosmic IHH who did not undergo puberty and in whom luteinizing hormone (LH; see 152780) was undetectable, Cole et al. (2008) identified heterozygosity for the R73C mutation in the PROK2 gene. Functional analysis in CHO cells demonstrated a 7-fold decrease in calcium-mobilizing activity with the R73C mutant at the EC50 of wildtype. The patient reported a normal sense of smell; additional features included diabetes mellitus and osteoporosis.
In a female patient with Kallmann syndrome (HH4; 610628), Cole et al. (2008) identified a heterozygous c.70G-C transversion in exon 1 of the PROK2 gene, resulting in an ala24-to-pro (A24P) substitution in the signal peptide region, as well as a heterozygous missense mutation in the PROKR2 gene (V115M; 607123.0007). The patient did not undergo puberty, and luteinizing hormone (LH; see 152780) was undetectable. Olfactory bulbs were absent on MRI. Other features included strabismus, hearing loss, short fourth metacarpal, pes planus, learning disability, and sleep disorder.
In 2 brothers with Kallmann syndrome (HH4; 610628), Cole et al. (2008) identified heterozygosity for a c.101G-A transition in exon 2 of the PROK2 gene, resulting in a cys34-to-tyr (C34Y) substitution. Their asymptomatic mother was also heterozygous for the mutation. Functional analysis in HEK293 cells demonstrated that the C34Y substitution totally abolished calcium mobilization activity, with a 1,000-fold decrease in activity at the EC50 of wildtype.
Cheng, M. Y., Bullock, C. M., Li, C., Lee, A. G., Bermak, J. C., Belluzzi, J., Weaver, D. R., Leslie, F. M., Zhou, Q.-Y. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 417: 405-410, 2002. [PubMed: 12024206] [Full Text: https://doi.org/10.1038/417405a]
Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J. Clin. Endocr. Metab. 93: 3551-3559, 2008. [PubMed: 18559922] [Full Text: https://doi.org/10.1210/jc.2007-2654]
Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2: e175, 2006. Note: Electronic Article. [PubMed: 17054399] [Full Text: https://doi.org/10.1371/journal.pgen.0020175]
Giannini, E., Lattanzi, R., Nicotra, A., Campese, A. F., Grazioli, P., Screpanti, I., Balboni, G., Salvadori, S., Sacerdote, P., Negri, L. The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain. Proc. Nat. Acad. Sci. 106: 14646-14651, 2009. [PubMed: 19667192] [Full Text: https://doi.org/10.1073/pnas.0903720106]
Hanchate, N. K., Giacobini, P., Lhuillier, P., Parkash, J., Espy, C., Fouveaut, C., Leroy, C., Baron, S., Campagne, C., Vanacker, C., Collier, F., Cruaud, C, and 12 others. SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet. 8: e1002896, 2012. Note: Electronic Article. [PubMed: 22927827] [Full Text: https://doi.org/10.1371/journal.pgen.1002896]
Jilek, A., Engel, E., Beier, D., Lepperdinger, G. Murine Bv8 gene maps near a synteny breakpoint of mouse chromosome 6 and human 3p21. Gene 256: 189-195, 2000. [PubMed: 11054548] [Full Text: https://doi.org/10.1016/s0378-1119(00)00355-3]
Leroy, C., Fouveaut, C., Leclercq, S., Jacquemont, S., Du Boullay, H., Lespinasse, J., Delpech, M., Dupont, J.-M., Hardelin, J.-P., Dode, C. Biallelic mutations in the prokineticin-2 gene in two sporadic cases of Kallmann syndrome. Europ. J. Hum. Genet. 16: 865-868, 2008. [PubMed: 18285834] [Full Text: https://doi.org/10.1038/ejhg.2008.15]
Li, M., Bullock, C. M., Knauer, D. J., Ehlert, F. J., Zhou, Q. Y. Identification of two prokineticin cDNAs: recombinant proteins potently contract gastrointestinal smooth muscle. Molec. Pharm. 59: 692-698, 2001. [PubMed: 11259612] [Full Text: https://doi.org/10.1124/mol.59.4.692]
Ng, K. L., Li, J.-D., Cheng, M. Y., Leslie, F. M., Lee, A. G., Zhou, Q.-Y. Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science 308: 1923-1927, 2005. [PubMed: 15976302] [Full Text: https://doi.org/10.1126/science.1112103]
Pitteloud, N., Zhang, C., Pignatelli, D., Li, J.-D., Raivio, T., Cole, L. W., Plummer, L., Jacobson-Dickman, E. E., Mellon, P. L., Zhou, Q.-Y., Crowley, W. F., Jr. Loss-of-function mutation in the prokineticin 2 gene causes Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism. Proc. Nat. Acad. Sci. 104: 17447-17452, 2007. [PubMed: 17959774] [Full Text: https://doi.org/10.1073/pnas.0707173104]
Shojaei, F., Wu, X., Zhong, C., Yu, L., Liang, X.-H., Yao, J., Blanchard, D., Bais, C., Peale, F. V., van Bruggen, N., Ho, C., Ross, J., Tan, M., Carano, R. A. D., Meng, Y. G., Ferrara, N. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature 450: 825-831, 2007. [PubMed: 18064003] [Full Text: https://doi.org/10.1038/nature06348]