• PMID: 24276467
• Gene Name: PROKR2
• Condition: Hypogonadism
• Association: 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.
• Mutation: p.V158I, p.V334M, p.L173R, p.T260M, p.R268C, p.V274D, p.V331M, p.H20MfsX23 and p.N15TfsX30
• Population size: 246
• Population details: 246 hypogonadism
• Sex: Male, female
• Infertility type: Male infertility, Female infertility
• Other associated phenotypes: Hypogonadism

Germline prokineticin receptor 2 (PROKR2) variants associated with central hypogonadism cause differental modulation of distinct intracellular pathways

Libri DV, Kleinau G, Vezzoli V, Busnelli M, Guizzardi F, Sinisi AA, Pincelli AI, Mancini A, Russo G, Beck-Peccoz P, Loche S, Crivellaro C, Maghnie M, Krausz C, Persani L, Bonomi M; Italian Study Group on Idiopathic Central Hypogonadism (ICH).

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. FAU - Libri, Domenico Vladimiro AU - Libri DV AD - Unità 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. FAU - Kleinau, Gunnar AU - Kleinau G FAU - Vezzoli, Valeria AU - Vezzoli V FAU - Busnelli, Marta AU - Busnelli M FAU - Guizzardi, Fabiana AU - Guizzardi F FAU - Sinisi, Antonio Agostino AU - Sinisi AA FAU - Pincelli, Angela Ida AU - Pincelli AI FAU - Mancini, Antonio AU - Mancini A FAU - Russo, Gianni AU - Russo G FAU - Beck-Peccoz, Paolo AU - Beck-Peccoz P FAU - Loche, Sandro AU - Loche S FAU - Crivellaro, Claudio AU - Crivellaro C FAU - Maghnie, Mohamad AU - Maghnie M FAU - Krausz, Csilla AU - Krausz C FAU - Persani, Luca AU - Persani L