Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors

Research output: Contribution to journalArticle

Authors

  • Kelly L Roszko
  • Ruiye Bi
  • Hans Bräuner-Osborne
  • Xiao-Feng Xiong
  • Asuka Inoue
  • Rajesh V Thakker
  • Kristian Strømgaard
  • Thomas Gardella
  • Michael Mannstadt

Colleges, School and Institutes

External organisations

  • Endocrine Unit, Massachusetts General Hospital and Harvard Medical School. 50 Blossom St, Thier 11, Boston, MA, 02114, USA. Electronic address: demay@helix.mgh.harvard.edu.
  • Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
  • Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, England, United Kingdom.
  • Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
  • Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, Japan.

Abstract

Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα11 in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutation GNA11 c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11R6OC is partly dependent on coupling to the CASR. Treatment with the Gα11/q-specific inhibitor YM-254890 increased blood calcium in heterozygous but not in homozygous GNA11R60C mice, consistent with published crystal structure data showing that Arg60 forms a critical contact with YM-254890. This animal model of ADH2 provides insights into molecular mechanism of this G protein-related disease and potential paths toward new lines of therapy.

Details

Original languageEnglish
Pages (from-to)e91079
JournalJCI Insight
Volume2
Issue number3
Publication statusPublished - 9 Feb 2017