Alternative titles; symbols
HGNC Approved Gene Symbol: PROKR2
Cytogenetic location: 20p12.3 Genomic coordinates (GRCh38): 20:5,299,218-5,316,954 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p12.3 | Hypogonadotropic hypogonadism 3 with or without anosmia | 244200 | Autosomal dominant | 3 |
Lin et al. (2002) cloned human GPR73L1 (PROKR2) by PCR of a pooled testis and fetal brain cDNA library. They also cloned GPR73 (PROKR1; 607122), which shares 85% overall sequence identity with GPR73L1. The greatest divergence between the proteins is in the N terminus, and both share about 80% sequence identity with mouse Gpr73. RT-PCR detected expression of GPR73L1 in brain, testis, small intestine, ovary, thyroid, pituitary, and salivary gland. Expression in the small intestine was confined to the ileocecum.
Lin et al. (2002) transfected GPR73 and GPR73L1 into Chinese hamster ovary cells and found that both proteins are receptors for prokineticins (see PROK1, 606233). Both proteins mobilized calcium when exposed to nanomolar concentrations of recombinant PROK1 and PROK2 (607002), and the calcium response was insensitive to pertussis toxin, suggesting that the proteins couple exclusively to Gq (600998) rather than to Gi/o (see GNAO1, 139311). PROK1 produced a dose-dependent increase in total inositol phosphate concentrations in transiently transfected COS-7 cells, but neither GPR had an effect on adenylate cyclase (see ADCY3, 600291). PROK1 induced sustained phosphorylation of p44/p42 MAPK (see MAPK3, 601795) in cells transfected with GPR73, but not in cells transfected with GPR73L1. PROK2 stimulated MAPK3 phosphorylation in cells transfected with both GPRs.
Lin et al. (2002) mapped the PROKR2 gene in silico to chromosome 20p13.
Kallmann syndrome (see HH3; 244200) 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 10 and 4 different point mutations in the PROKR2 gene and in one of its ligands, PROK2. The mutations in PROKR2 (e.g., 607123.0001-607123.0005 and 607123.0008) were detected in heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation (607123.0001) was also heterozygous for a mutation in the KAL1 gene (300836.0012), suggesting possible digenic inheritance. The findings of Dode et al. (2006) demonstrated that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. Dode et al. (2006) noted that some of the mutations identified in the PROK2 and PROKR2 genes were detected in clinically unaffected individuals, indicating that additional genetic or nongenetic factors are involved in disease production.
In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., 607123.0001 and 607123.0006-607123.0009); 1 of the probands (see 607123.0007) also carried a heterozygous mutation in PROK2 (607002.0005). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH; screening of 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 PROKR2 can cause both Kallmann syndrome and normosmic IHH.
By site-directed mutagenesis, Monnier et al. (2009) introduced human PROKR2 missense mutations identified in Kallmann syndrome patients into the mouse Prokr2 gene and tested their effects on signaling activity in transfected HEK293 cells by measuring intracellular calcium release upon ligand activation of the receptor. All mutated receptors except one (M323I; 607123.0005) had decreased signaling activities. The mutations L173R (607123.0001), W178S (607123.0008), and P290S impaired cell-surface targeting of the receptor. The Q210R mutation (607123.0002) abolished ligand binding. Five mutations (R85C, R85H (607123.0003), R164Q, R268C, V331M) presumably impaired G protein coupling of the receptor. When wildtype and mutant receptors were coexpressed in HEK293 cells, none of the intracellularly retained mutant receptors affected cell surface-targeting of the wildtype receptor, and none of the mutant receptors properly addressed at the plasma membrane affected wildtype receptor signaling activity. Monnier et al. (2009) concluded that their results argued against a dominant-negative effect of the mutations in vivo.
In 2 patients with anosmic hypogonadotropic hypogonadism (HH16; 614897) who were heterozygous for 2 different missense mutations in the SEMA3A gene (603961), Hanchate et al. (2012) also identified heterozygosity for a missense mutation in PROKR2. The authors concluded that their findings further substantiated the oligogenic pattern of inheritance in this developmental disorder.
Matsumoto et al. (2006) found that deletion of the Pkr2 gene in mice led to hypoplasia of the olfactory bulb and reproductive system, including testis, ovary, uterus, vagina, and mammary gland. In Pkr2 -/- mice, plasma levels of testosterone and follicle-stimulating hormone (see FSHB; 136530) were decreased, and the mRNA levels of gonadotropin-releasing hormone (see GNRH1; 152760) in the hypothalamus and luteinizing hormone (see LHB; 152780) and follicle-stimulating hormone in the pituitary were also significantly reduced. Immunohistochemical analysis revealed that GNRH neurons were absent in the hypothalamus in Pkr2 -/- mice. Matsumoto et al. (2006) noted that the phenotype was similar to the clinical features of Kallmann syndrome.
Prosser et al. (2007) found that Prokr2 -/- mice demonstrated partially penetrant postnatal lethality and that surviving mice weighed significantly less than wildtype. Prokr2 -/- mice failed to breed, and they were hypokinetic and lost precision in the timing and onset of nocturnal locomotor activity compared to Prokr +/- mice and wildtype mice. Under both a light/dark cycle and continuous darkness, Prokr -/- mice showed a pronounced temporal redistribution of activity away from early to late circadian night, and they demonstrated disturbed regulation of core body temperature rhythm. In vitro studies of suprachiasmatic nucleus (SCN) slices showed normal circadian oscillation as demonstrated by bioluminescent real-time imaging. Prosser et al. (2007) concluded that Prokr2 is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.
Dode et al. (2006) identified a 518T-G transversion in exon 2 of the PROKR2 gene, resulting in a leu173-to-arg (L173R) substitution, in patients with Kallmann syndrome (HH3; 244200). The mutation was found in heterozygous state in a family and in 3 sporadic cases, in homozygous state in a sporadic case, and in compound heterozygous state with a Q210R mutation (607123.0002) in another family. In a sporadic case of Kallmann syndrome, Dode et al. (2006) found heterozygosity for L173R as well as heterozygosity for a mutation in the KAL1 gene (300836.0012), suggesting digenic inheritance. The L173R and Q210R mutations in the PROKR2 gene were not found in 500 ethnically matched (Caucasian) control alleles.
In 2 unrelated male patients with Kallmann syndrome, Cole et al. (2008) identified heterozygosity for the L173R mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the L173R mutant compared to wildtype in both assays. Both patients had complete absence of puberty with undetectable levels of luteinizing hormone (LH; 152780), and their sense of smell was below the fifth percentile on olfactory testing; MRI performed in 1 of the patients showed absence of the olfactory bulbs. Additional features included pes planus, pectus excavatum, and synkinesia in 1 patient and cryptorchidism in the other.
Monnier et al. (2009) performed functional analysis of the L173R mutation in HEK293 cells and demonstrated decreased signaling and impaired cell-surface targeting of the receptor compared to wildtype.
For discussion of the gln210-to-arg (Q210R) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with Kallmann syndrome (HH3; 244200) by Dode et al. (2006), see 607123.0001.
Monnier et al. (2009) performed functional analysis of the Q210R mutation in HEK293 cells and demonstrated that the mutation abolished ligand binding.
In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 254G-A transition in exon 1 of the PROKR2 gene, resulting in an arg85-to-his (R85H) substitution. They identified the same mutation in homozygous state in a sporadic case of Kallmann syndrome.
Monnier et al. (2009) performed functional analysis of the R85H mutation in HEK293 cells and observed decreased signaling activity compared to wildtype.
In affected members of a family with Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a 1-bp deletion (58delC) in exon 1 of the PROKR2 gene, causing a frameshift resulting in a premature termination codon (20fsTer43). In another family with Kallmann syndrome, they found the same mutation in compound heterozygous state with a 969G-A transition resulting in an M323I substitution (607123.0005).
For discussion of the met323-to-ile (M323I) mutation in the PROKR2 gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism-3 with anosmia (HH3; 244200) by Dode et al. (2006), see 607123.0004.
In a female patient with normosmic hypogonadotropic hypogonadism (HH3; 244200), Cole et al. (2008) identified heterozygosity for a c.253C-T transition in the PROKR2 gene, resulting in an arg85-to-cys (R85C) substitution within the first intracellular loop. Functional analysis demonstrated significantly decreased intracellular calcium mobilization with the R85C mutant compared to wildtype. The mutation was not found in 346 control alleles; Dode et al. (2006) stated that they detected R85C in 1 of 500 Caucasian control alleles. The patient underwent partial puberty, with primary amenorrhea, but she had Tanner stage IV breast development and exhibited GnRH (152760)-induced luteinizing hormone (LH; see 152780) secretion in the setting of a low-normal estradiol level while still amenorrheic. She had a normal sense of smell on olfactory testing, and MRI showed normal olfactory bulbs. Both of her parents had delayed puberty; their mutation status was not reported.
In a female patient with Kallmann syndrome (HH3; 244200), Cole et al. (2008) identified a heterozygous c.343G-A transition in the PROKR2 gene, resulting in a val115-to-met (V115M) substitution within the first extracellular loop; in addition, a heterozygous mutation in the PROK2 gene (A24P; 607002.0005) was detected. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the V115M mutant compared to wildtype in both assays. 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 a patient with sporadic Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a c.533G-C transversion in exon 2 of the PROKR2 gene, resulting in a trp178-to-ser (W178S) substitution in the T4 domain. The mutation was not found in 500 ethnically matched (Caucasian) alleles.
In a male patient with normosmic hypogonadotropic hypogonadism, Cole et al. (2008) identified heterozygosity for the W178S mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the W178S mutant compared to wildtype in both assays. The patient did not undergo puberty and had a normal sense of smell on olfactory testing. He exhibited a pulsatile pattern of luteinizing hormone (LH; see 152780) and had elevated LH and follicle-stimulating hormone (FSH; see 136435) levels in the setting of hypogonadal testosterone levels. Cole et al. (2008) noted that the LH secretion pattern was hypergonadotropic, although not in the range of males with primary gonadal failure, suggesting a dual hypothalamic and gonadal defect that involved insufficient GNRH (152760) secretion as well as primary gonadal resistance.
Monnier et al. (2009) performed functional analysis of the W178S mutation in HEK293 cells and observed impaired cell-surface targeting of the receptor with the W178S mutant compared to wildtype.
In a male patient with normosmic hypogonadotropic hypogonadism (HH3; 244200) who experienced reversal of his hypogonadism later in life, Cole et al. (2008) identified heterozygosity for a c.743G-A transition in the PROKR2 gene, resulting in an arg248-to-gln (R248Q) substitution within the last intracellular loop. The mutation was present in heterozygosity in the patient's unaffected father, but was not found in 346 control alleles. Functional analysis demonstrated decreased activity on calcium mobilization assay with the R248Q mutant compared to wildtype. The patient underwent partial puberty with some testicular growth (testicular volume, 6-7 ml) evident at the time of diagnosis. At 28 years of age, after discontinuation of testosterone therapy, he achieved fertility and sustained normal serum testosterone levels thereafter.
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]
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]
Lin, D. C.-H., Bullock, C. M., Ehlert, F. J., Chen, J.-L., Tian, H., Zhou, Q.-Y. Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J. Biol. Chem. 277: 19276-19280, 2002. [PubMed: 11886876] [Full Text: https://doi.org/10.1074/jbc.M202139200]
Matsumoto, S., Yamazaki, C., Masumoto, K., Nagano, M., Naito, M., Soga, T., Hiyama, H., Matsumoto, M., Takasaki, J., Kamohara, M., Matsuo, A., Ishii, H., Kobori, M., Katoh, M., Matsushime, H., Furuichi, K., Shigeyoshi, Y. Abnormal development of the olfactory bulb and reproductive system in mice lacking prokineticin receptor PKR2. Proc. Nat. Acad. Sci. 103: 4140-4145, 2006. [PubMed: 16537498] [Full Text: https://doi.org/10.1073/pnas.0508881103]
Monnier, C., Dode, C., Fabre, L., Teixeira, L., Labesse, G., Pin, J.-P., Hardelin, J.-P., Rondard, P. PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum. Molec. Genet. 18: 75-81, 2009. [PubMed: 18826963] [Full Text: https://doi.org/10.1093/hmg/ddn318]
Prosser, H. M., Bradley, A., Chesham, J. E., Ebling, F. J. P., Hastings, M. H., Maywood, E. S. Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc. Nat. Acad. Sci. 104: 648-563, 2007. [PubMed: 17202262] [Full Text: https://doi.org/10.1073/pnas.0606884104]