Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

Caroline M. Gorvin, Fadil M. Hannan, Sarah A. Howles, Valerie N. Babinsky, Sian E. Piret, Angela Rogers, Andrew J. Freidin, Michelle Stewart, Anju Paudyal, Tertius A. Hough, M. Andrew Nesbit, Sara Wells, Tonia L. Vincent, Stephen D.M. Brown, Roger D. Cox, Rajesh V. Thakker

Research output: Contribution to journalArticle

Abstract

Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available, and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesized that a previously reported dark skin mouse mutant (Dsk7) — which has a germline hypermorphic Gα11 mutation, Ile62Val — may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain of function. Treatment with NPS-2143, a calcilytic compound, normalized these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.
LanguageEnglish
JournalJCI Insight
Volume2
Issue number3
DOIs
Publication statusPublished - 9 Feb 2017

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Hypocalcemia
Protein Subunits
GTP-Binding Proteins
Mutation
Calcium-Sensing Receptors
Parathyroid Hormone
Therapeutics
Calcium Signaling
Familial Hypercalciuric Hypocalcemia
Up-Regulation
Calcium
Skin

Keywords

  • mutation
  • hypocalcaemia

Cite this

Gorvin, C. M., Hannan, F. M., Howles, S. A., Babinsky, V. N., Piret, S. E., Rogers, A., ... Thakker, R. V. (2017). Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight, 2(3). https://doi.org/10.1172/jci.insight.91103
Gorvin, Caroline M. ; Hannan, Fadil M. ; Howles, Sarah A. ; Babinsky, Valerie N. ; Piret, Sian E. ; Rogers, Angela ; Freidin, Andrew J. ; Stewart, Michelle ; Paudyal, Anju ; Hough, Tertius A. ; Nesbit, M. Andrew ; Wells, Sara ; Vincent, Tonia L. ; Brown, Stephen D.M. ; Cox, Roger D. ; Thakker, Rajesh V. / Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. In: JCI Insight. 2017 ; Vol. 2, No. 3.
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abstract = "Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available, and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesized that a previously reported dark skin mouse mutant (Dsk7) — which has a germline hypermorphic Gα11 mutation, Ile62Val — may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain of function. Treatment with NPS-2143, a calcilytic compound, normalized these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.",
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Gorvin, CM, Hannan, FM, Howles, SA, Babinsky, VN, Piret, SE, Rogers, A, Freidin, AJ, Stewart, M, Paudyal, A, Hough, TA, Nesbit, MA, Wells, S, Vincent, TL, Brown, SDM, Cox, RD & Thakker, RV 2017, 'Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy', JCI Insight, vol. 2, no. 3. https://doi.org/10.1172/jci.insight.91103

Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. / Gorvin, Caroline M.; Hannan, Fadil M.; Howles, Sarah A.; Babinsky, Valerie N.; Piret, Sian E.; Rogers, Angela; Freidin, Andrew J.; Stewart, Michelle; Paudyal, Anju; Hough, Tertius A.; Nesbit, M. Andrew; Wells, Sara; Vincent, Tonia L.; Brown, Stephen D.M.; Cox, Roger D.; Thakker, Rajesh V.

In: JCI Insight, Vol. 2, No. 3, 09.02.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

AU - Gorvin, Caroline M.

AU - Hannan, Fadil M.

AU - Howles, Sarah A.

AU - Babinsky, Valerie N.

AU - Piret, Sian E.

AU - Rogers, Angela

AU - Freidin, Andrew J.

AU - Stewart, Michelle

AU - Paudyal, Anju

AU - Hough, Tertius A.

AU - Nesbit, M. Andrew

AU - Wells, Sara

AU - Vincent, Tonia L.

AU - Brown, Stephen D.M.

AU - Cox, Roger D.

AU - Thakker, Rajesh V.

N1 - Compliant in UIR; evidence uploaded to 'Other files'

PY - 2017/2/9

Y1 - 2017/2/9

N2 - Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available, and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesized that a previously reported dark skin mouse mutant (Dsk7) — which has a germline hypermorphic Gα11 mutation, Ile62Val — may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain of function. Treatment with NPS-2143, a calcilytic compound, normalized these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.

AB - Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available, and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesized that a previously reported dark skin mouse mutant (Dsk7) — which has a germline hypermorphic Gα11 mutation, Ile62Val — may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant Dsk7/+ and Dsk7/Dsk7 mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11 to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain of function. Treatment with NPS-2143, a calcilytic compound, normalized these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations in Dsk7/Dsk7 and Dsk7/+ mice, which became normocalcemic. Thus, these studies have established Dsk7 mice, which harbor a germline gain-of-function Gα11 mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.

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Gorvin CM, Hannan FM, Howles SA, Babinsky VN, Piret SE, Rogers A et al. Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight. 2017 Feb 9;2(3). https://doi.org/10.1172/jci.insight.91103