Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation

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Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation. / Howles, Sarah A; Hannan, Fadil M; Gorvin, Caroline M; Piret, Sian E; Paudyal, Anju; Stewart, Michelle; Hough, Tertius A; Nesbit, M Andrew; Wells, Sara; Brown, Stephen Dm; Cox, Roger D; Thakker, Rajesh V.

In: JCI Insight, Vol. 2, No. 20, 19.10.2017.

Research output: Contribution to journalArticle

Harvard

Howles, SA, Hannan, FM, Gorvin, CM, Piret, SE, Paudyal, A, Stewart, M, Hough, TA, Nesbit, MA, Wells, S, Brown, SD, Cox, RD & Thakker, RV 2017, 'Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation', JCI Insight, vol. 2, no. 20. https://doi.org/10.1172/jci.insight.96540

APA

Howles, S. A., Hannan, F. M., Gorvin, C. M., Piret, S. E., Paudyal, A., Stewart, M., Hough, T. A., Nesbit, M. A., Wells, S., Brown, S. D., Cox, R. D., & Thakker, R. V. (2017). Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation. JCI Insight, 2(20). https://doi.org/10.1172/jci.insight.96540

Vancouver

Author

Howles, Sarah A ; Hannan, Fadil M ; Gorvin, Caroline M ; Piret, Sian E ; Paudyal, Anju ; Stewart, Michelle ; Hough, Tertius A ; Nesbit, M Andrew ; Wells, Sara ; Brown, Stephen Dm ; Cox, Roger D ; Thakker, Rajesh V. / Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation. In: JCI Insight. 2017 ; Vol. 2, No. 20.

Bibtex

@article{62f07d567a5d4612a73dea80aeaccd58,
title = "Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation",
abstract = "Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.",
author = "Howles, {Sarah A} and Hannan, {Fadil M} and Gorvin, {Caroline M} and Piret, {Sian E} and Anju Paudyal and Michelle Stewart and Hough, {Tertius A} and Nesbit, {M Andrew} and Sara Wells and Brown, {Stephen Dm} and Cox, {Roger D} and Thakker, {Rajesh V}",
year = "2017",
month = oct
day = "19",
doi = "10.1172/jci.insight.96540",
language = "English",
volume = "2",
journal = "JCI Insight",
issn = "2379-3708",
number = "20",

}

RIS

TY - JOUR

T1 - Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation

AU - Howles, Sarah A

AU - Hannan, Fadil M

AU - Gorvin, Caroline M

AU - Piret, Sian E

AU - Paudyal, Anju

AU - Stewart, Michelle

AU - Hough, Tertius A

AU - Nesbit, M Andrew

AU - Wells, Sara

AU - Brown, Stephen Dm

AU - Cox, Roger D

AU - Thakker, Rajesh V

PY - 2017/10/19

Y1 - 2017/10/19

N2 - Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.

AB - Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.

U2 - 10.1172/jci.insight.96540

DO - 10.1172/jci.insight.96540

M3 - Article

C2 - 29046478

VL - 2

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 20

ER -