Gα11 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy

Research output: Contribution to journalArticle

Authors

  • 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

Colleges, School and Institutes

External organisations

  • Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
  • Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.; Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
  • ARUK Centre for Osteoarthritis Pathogenesis, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
  • Mammalian Genetics Unit and Mary Lyon Centre, Medical Research Council (MRC) Harwell Institute
  • Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.; Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom.

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.

Details

Original languageEnglish
Pages (from-to)e91103
JournalJCI Insight
Volume2
Issue number3
Publication statusPublished - 9 Feb 2017