Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation.

Abstract

Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin-adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.

• Authors: Sarah A Howles, Fadil M Hannan, Caroline M Gorvin, Sian E Piret, Anju Paudyal, Michelle Stewart, Tertius A Hough, M Andrew Nesbit, Sara Wells, Stephen Dm Brown, Roger D Cox, Rajesh V Thakker
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 20 (10 19 2017) ISSN: 2379-3708 [Electronic] United States
• PMID: 29046478 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Parathyroid Hormone
• Receptors, Calcium-Sensing
• Serum Albumin
• GTP-Binding Protein alpha Subunits, Gq-G11
• Ethylnitrosourea
• Calcium
• Cinacalcet

Topics

• Administration, Oral
• Animals
• Calcium (blood, urine)
• Cinacalcet (administration & dosage, therapeutic use)
• Disease Models, Animal
• Ethylnitrosourea (pharmacology)
• Female
• GTP-Binding Protein alpha Subunits, Gq-G11 (chemistry, drug effects, genetics)
• Humans
• Hypercalcemia (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Models, Molecular
• Mutation (drug effects)
• Parathyroid Hormone (blood, metabolism)
• Receptors, Calcium-Sensing (metabolism)
• Sequence Alignment
• Sequence Analysis, DNA
• Serum Albumin
• Signal Transduction