| First Author | Gorvin CM | Year | 2017 |
| Journal | JCI Insight | Volume | 2 |
| Issue | 3 | Pages | e91103 |
| PubMed ID | 28194447 | Mgi Jnum | J:253619 |
| Mgi Id | MGI:6109097 | Doi | 10.1172/jci.insight.91103 |
| Citation | Gorvin CM, et al. (2017) Galpha11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy. JCI Insight 2(3):e91103 |
| abstractText | Heterozygous germline gain-of-function mutations of G-protein subunit alpha11 (Galpha11), 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 Galpha11 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 Galpha11 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 Galpha11 mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy. |
