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Germline ProkineticinReceptor 2 (PROKR2)Variants AssociatedWith CentralHypogonadism CauseDifferentalModulation ofDistinctIntracellularPathways Domenico LibriGunnar KleinauValeria Vezzoli2013 год

Germline Prokineticin Receptor 2 (PROKR2) Variants Associated With Central Hypogonadism Cause Differental Modulation of Distinct Intracellular Pathways
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Аннотация: 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.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).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.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.
Год издания: 2013
Авторы: Domenico Libri, Gunnar Kleinau, Valeria Vezzoli, Marta Busnelli, Fabiana Guizzardi, Antonio Agostino Sinisi, Angela Ida Pincelli, Antonio Mancini, Gianni Russo, Paolo Beck‐Peccoz, Sandro Loche, Claudio Crivellaro, Mohamad Maghnie, Csilla Krausz, Luca Persani, Marco Bonomi
Издательство: Oxford University Press
Источник: The Journal of Clinical Endocrinology & Metabolism
Ключевые слова: Hypothalamic control of reproductive hormones, Regulation of Appetite and Obesity, Biotin and Related Studies
Другие ссылки: The Journal of Clinical Endocrinology & Metabolism (PDF)
The Journal of Clinical Endocrinology & Metabolism (HTML)
Florence Research (University of Florence) (PDF)
Florence Research (University of Florence) (HTML)
Institutional Research Information System University of Turin (University of Turin) (PDF)
Institutional Research Information System University of Turin (University of Turin) (HTML)
PubMed (HTML)