Gα<sub>11</sub> mutation in mice causes hypocalcemia rectifiable by calcilytic therapy



Gorvin, Caroline M, Hannan, Fadil M ORCID: 0000-0002-2975-5170, Howles, Sarah A, Babinsky, Valerie N, Piret, Sian E, Rogers, Angela, Freidin, Andrew J, Stewart, Michelle, Paudyal, Anju, Hough, Tertius A
et al (show 6 more authors) (2017) Gα<sub>11</sub> mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI INSIGHT, 2 (3). e91103-.

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Abstract

Heterozygous germline gain-of-function mutations of G-protein subunit α<sub>11</sub> (Gα<sub>11</sub>), 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 (<i>Dsk7</i>) - which has a germline hypermorphic Gα<sub>11</sub> 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 <i>Dsk7/+</i> and <i>Dsk7/Dsk7</i> mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα<sub>11</sub> 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 <i>Dsk7/Dsk7</i> and <i>Dsk7/+</i> mice, which became normocalcemic. Thus, these studies have established <i>Dsk7</i> mice, which harbor a germline gain-of-function Gα<sub>11</sub> mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.

Item Type: Article
Uncontrolled Keywords: Animals, Humans, Mice, Hypocalcemia, Hypoparathyroidism, Disease Models, Animal, Calcium, Naphthalenes, Parathyroid Hormone, GTP-Binding Protein alpha Subunits, Receptors, G-Protein-Coupled, Receptors, Calcium-Sensing, MAP Kinase Signaling System, Mutation, Hypercalciuria, HEK293 Cells
Depositing User: Symplectic Admin
Date Deposited: 16 Feb 2017 11:15
Last Modified: 06 Oct 2023 11:17
DOI: 10.1172/jci.insight.91103
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3005859