11 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 journalArticlepeer-review

149 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)e91103
JournalJCI Insight
Issue number3
Publication statusPublished - 9 Feb 2017


Dive into the research topics of 'Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy'. Together they form a unique fingerprint.

Cite this