Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

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 (<i>Dsk7</i>) - 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 <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 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 <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 Gα₁₁ mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.