Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice

Abstract GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targete...

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Autores principales:	Min Pi, Fuyi Xu, Ruisong Ye, Satoru K. Nishimoto, Robert A. Kesterson, Robert W. Williams, Lu Lu, L. Darryl Quarles
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3ed251cfeccd48bdb84fed80a49a4f2a
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spelling	oai:doaj.org-article:3ed251cfeccd48bdb84fed80a49a4f2a2021-12-02T15:39:40ZHumanized GPRC6A KGKY is a gain-of-function polymorphism in mice10.1038/s41598-020-68113-z2045-2322https://doaj.org/article/3ed251cfeccd48bdb84fed80a49a4f2a2020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-68113-zhttps://doaj.org/toc/2045-2322Abstract GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create Gprc6a- KGKY-knockin mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. Gprc6a- KGKY-knockin mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of Gprc6a- KGKY-knockin mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A- KGKY variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice.Min PiFuyi XuRuisong YeSatoru K. NishimotoRobert A. KestersonRobert W. WilliamsLu LuL. Darryl QuarlesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Min Pi Fuyi Xu Ruisong Ye Satoru K. Nishimoto Robert A. Kesterson Robert W. Williams Lu Lu L. Darryl Quarles Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
description	Abstract GPRC6A is proposed to regulate energy metabolism in mice, but in humans a KGKY polymorphism in the third intracellular loop (ICL3) is proposed to result in intracellular retention and loss-of-function. To test physiological importance of this human polymorphism in vivo, we performed targeted genomic humanization of mice by using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9) system to replace the RKLP sequence in the ICL3 of the GPRC6A mouse gene with the uniquely human KGKY sequence to create Gprc6a- KGKY-knockin mice. Knock-in of a human KGKY sequence resulted in a reduction in basal blood glucose levels and increased circulating serum insulin and FGF-21 concentrations. Gprc6a- KGKY-knockin mice demonstrated improved glucose tolerance, despite impaired insulin sensitivity and enhanced pyruvate-mediated gluconeogenesis. Liver transcriptome analysis of Gprc6a- KGKY-knockin mice identified alterations in glucose, glycogen and fat metabolism pathways. Thus, the uniquely human GPRC6A- KGKY variant appears to be a gain-of-function polymorphism that positively regulates energy metabolism in mice.
format	article
author	Min Pi Fuyi Xu Ruisong Ye Satoru K. Nishimoto Robert A. Kesterson Robert W. Williams Lu Lu L. Darryl Quarles
author_facet	Min Pi Fuyi Xu Ruisong Ye Satoru K. Nishimoto Robert A. Kesterson Robert W. Williams Lu Lu L. Darryl Quarles
author_sort	Min Pi
title	Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
title_short	Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
title_full	Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
title_fullStr	Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
title_full_unstemmed	Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice
title_sort	humanized gprc6a kgky is a gain-of-function polymorphism in mice
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/3ed251cfeccd48bdb84fed80a49a4f2a
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Humanized GPRC6A KGKY is a gain-of-function polymorphism in mice

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