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 (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.

• Authors: 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 Dm Brown, Roger D Cox, Rajesh V Thakker
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 3 Pg. e91103 (02 09 2017) ISSN: 2379-3708 [Print] United States
• PMID: 28194447 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASR protein, mouse
• GNA11 protein, mouse
• GTP-Binding Protein alpha Subunits
• N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
• Naphthalenes
• Parathyroid Hormone
• Receptors, Calcium-Sensing
• Receptors, G-Protein-Coupled
• Calcium

Topics

• Animals
• Calcium (blood)
• Disease Models, Animal
• GTP-Binding Protein alpha Subunits (genetics)
• HEK293 Cells
• Humans
• Hypercalciuria (drug therapy, genetics, metabolism)
• Hypocalcemia (drug therapy, genetics, metabolism)
• Hypoparathyroidism (congenital, drug therapy, genetics, metabolism)
• MAP Kinase Signaling System (drug effects)
• Mice
• Mutation
• Naphthalenes (administration & dosage, pharmacology)
• Parathyroid Hormone (blood)
• Receptors, Calcium-Sensing
• Receptors, G-Protein-Coupled (metabolism)