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Updated: May 5, 2026
Mutagenesis and Analysis of Genetic Mutations in the GC-rich KISS1 Receptor Sequence Identified in Humans with Reproductive Disorders
Published on: September 4, 2011
Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation
Domenico Vladimiro Libri1, Gunnar Kleinau, Valeria Vezzoli
1Unità di Medicina Generale ad Indirizzo Endocrino-Metabolico e Laboratorio di Ricerche Endocrino-Metaboliche (D.V.L., F.G., L.P., M.Bo.), Istituto Auxologico Italiano, 20149 Milano, Italy; Institute of Experimental Pediatric Endocrinology (G.K.), Charité-Universitätsmedizin, 10117 Berlin, Germany; Dipartimento di Scienze Cliniche e di Comunità (V.V., P.B.-P., L.P.), Università degli Studi di Milano, 20122 Milano, Italy; Consiglio Nazionale delle Ricerche (M.Bu.), Istituto di Neuroscienze, 20129 Milano, Italy; Dipartimento di Scienze Cardiotoraciche e Respiratorie (A.A.S.), Seconda Università di Napoli, 81100 Napoli, Italy; Clinica Medica, AO "San Gerardo dei Tintori" (A.I.P.), Università Milano-Bicocca, 20126 Monza, Italy; Divisione di Endocrinologia (A.M.), Dipartimento di Medicina Interna, Università del Sacro Cuore, 00168 Roma, Italy; Dipartimento di Pediatria (G.R.), Ospedale San Raffaele, 20132 Milano, Italy; Unità di Endocrinologia e Diabetologia (P.B.-P.), Fondazione Policlinico "Cà Granda," 20122 Milano, Italy; Servizio di Endocrinologia Pediatrica (S.L.), Ospedale Microcitemico, ASL Cagliari, 09121 Cagliari, Italy; Ospedale Regionale di Bolzano, 39100 Bolzano, Italy; Dipartimento di Pediatria (M.M.), G. Gaslini, Università di Genova, 16147 Genova, Italy; and Dipartimento di Fisiopatologia Clinica (C.K.), Unità di Andrologia, Università di Firenze, 50121 Firenze, Italy.
Introduction:
Defects of prokineticin pathway affect the neuroendocrine control of reproduction, but their role in the pathogenesis of central hypogonadism remains undefined, and the functional impact of the missense PROKR2 variants has been incompletely characterized.
Material And Methods:
In a series of 246 idiopathic central hypogonadism patients, we found three novel (p.V158I, p.V334M, and p.N15TfsX30) and six already known (p.L173R, p.T260M, p.R268C, p.V274D, p.V331M, and p.H20MfsX23) germline variants in the PROKR2 gene. We evaluated the effects of seven missense alterations on two different prokineticin receptor 2 (PROKR2)-dependent pathways: inositol phosphate-Ca(2+) (Gq coupling) and cAMP (Gs coupling).
Results:
PROKR2 variants were found in 16 patients (6.5%). Expression levels of variants p.V158I and p.V331M were moderately reduced, whereas they were markedly impaired in the remaining cases, except p.V334M, which was significantly overexpressed. The variants p.T260M, p.R268C, and p.V331M showed no remarkable changes in cAMP response (EC50) whereas the IP signaling appeared more profoundly affected. In contrast, cAMP accumulation cannot be stimulated through the p.L173R and p.V274D, but IP EC50 was similar to wt inp.L173R and increased by 10-fold in p.V274D. The variant p.V334M led to a 3-fold increase of EC50 for both cAMP and IP.
Conclusion:
Our study shows that single PROKR2 missense allelic variants can either affect both signaling pathways differently or selectively. Thus, the integrity of both PROKR2-dependent cAMP and IP signals should be evaluated for a complete functional testing of novel identified allelic variants.
Insights
Genetic variants in the prokineticin receptor 2 (PROKR2) gene are linked to central hypogonadism. Functional analysis revealed that PROKR2 missense variants differentially impact cAMP and inositol phosphate signaling pathways.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Prokineticin pathway defects impact reproductive neuroendocrine control.
- The role of these defects in central hypogonadism and the functional impact of PROKR2 variants are not fully understood.
Purpose of the Study:
- To investigate the role of PROKR2 gene variants in idiopathic central hypogonadism.
- To functionally characterize missense PROKR2 variants in relation to Gq (inositol phosphate-Ca2+) and Gs (cAMP) signaling pathways.
Main Methods:
- Screened 246 patients with idiopathic central hypogonadism for PROKR2 germline variants.
- Identified novel and known PROKR2 variants.
- Assessed the functional impact of seven missense variants on PROKR2-dependent inositol phosphate-Ca2+ and cAMP signaling pathways.
Main Results:
- PROKR2 variants were identified in 6.5% of patients.
- Variant expression levels varied from moderately reduced to significantly overexpressed.
- Missense variants differentially affected inositol phosphate and cAMP signaling, with some variants impacting both pathways selectively or differently.
Conclusions:
- Single PROKR2 missense variants can selectively or differentially affect cAMP and inositol phosphate signaling.
- Comprehensive functional testing of novel PROKR2 variants requires evaluation of both cAMP and inositol phosphate signals.
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