GERMLINE PROKINETICIN RECEPTOR 2 (PROKR2) VARIANTS ASSOCIATED WITH CENTRAL HYPOGONADISM CAUSE DIFFERENTAL MODULATION OF DISTINCT INTRACELLULAR PATHWAYS.

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RESEARCH PRODUCT

GERMLINE PROKINETICIN RECEPTOR 2 (PROKR2) VARIANTS ASSOCIATED WITH CENTRAL HYPOGONADISM CAUSE DIFFERENTAL MODULATION OF DISTINCT INTRACELLULAR PATHWAYS.

Domenico Vladimiro Libri Kleinau Gunnar Vezzoli Valeria Busnelli Marta Guizzardi Fabiana Antonio Agostino Sinisi Angela Ida Pincelli Mancini Antonio Russo Gianni Paolo Beck Peccoz Loche Sandro Crivellaro Claudio Mohamad Maghnie Krausz Csilla Persani Luca Bonomi Marco G. Aimaretti M. Altobelli G. Arnaldi M. Baldi L. Bartalena L. Beccaria G. Bellastella M. Bellizzi G. Bona G. Borretta F. Buzi S. Cannavo M. Cappa A. Cariboni T. Ciampani A. Cicognani M. Cisternino S. Corbetta N. Corciulo G. Corona R. Cozzi A. V. D'elia E. Degli Uberti M. De Marchi G. Forti N. Di Iorgi Andrea Isidori A. Fabbri A. Ferlin C. Foresta R. Franceschi A. Garolla R. Gaudino V. Giagulli E. Grosso E. Jannini F. Lanfranco L. Larizza A. Lenzi Francesco Lombardo P. Limone M. Maggi R. Maggi M. C. Maggio G. Mandrile M. Marino M. A. Mencarelli N. Migone G. Neri L. Perroni E. Pignatti A. Pilotta A. Pizzocaro A. Pontecorvi G. Pozzobon F. Prodam G. Radetti P. Razzore M. C. Salerno A. Salvatoni F. Salvini A. Secco Maria Segni M. Simoni R. Vigneri G. Weber

subject

Male Kallmann syndrome Endocrinology Diabetes and Metabolism Clinical Biochemistry Inositol Phosphate medicine.disease_cause Biochemistry Hypogonadotropic hypogonadism Germline Receptors G-Protein-Coupled Cohort Studies Endocrinology Settore MED/38 - Pediatria Generale E Specialistica Adolescent; Adult; Child; Cohort Studies; Cyclic AMP; Female; Genetic Association Studies; Humans; Hypogonadism; Inositol Phosphates; Male; Middle Aged; Mutation Missense; Receptors G-Protein-Coupled; Receptors Peptide; Signal Transduction; Young Adult; Germ-Line Mutation Receptors Cyclic AMP mutations; Kallmann syndrome; septo-optic dysplasia Missense mutation Receptor Child Mutation Middle Aged Prokineticin Peptide Female Human Signal Transduction Adult medicine.medical_specialty Receptors Peptide Adolescent Adolescent Adult Child Cohort Studies Cyclic AMP; metabolism Female Genetic Association Studies Germ-Line Mutation Humans Hypogonadism; epidemiology/genetics Inositol Phosphates; metabolism Male Middle Aged Missense Receptors; G-Protein-Coupled; genetics Receptors; Peptide; genetics Signal Transduction; genetics Young Adult Inositol Phosphates Mutation Missense Genetic Association Studie Biology G-Protein-Coupled Young Adult Germline mutation Internal medicine septo-optic dysplasia medicine Humans Genetic Association Studies Germ-Line Mutation Hypogonadism Biochemistry (medical)Kallmann syndrome Prokineticin receptor 2 medicine.disease PROKR2 hypogonadism prokineticin mutations Adolescent; Adult; Child; Cohort Studies; Cyclic AMP; Female; Genetic Association Studies; Humans; Hypogonadism; Inositol Phosphates; Male; Middle Aged; Mutation; Missense; Receptors; G-Protein-Coupled; Peptide; Signal Transduction; Young Adult; Germ-Line Mutation Endocrinology Mutation Cohort Studie Missense

description

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.

year	journal	country	edition	language
2013-11-27

10.1210/jc.2013-2431 http://hdl.handle.net/2318/151619