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Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors
Kelly L. Roszko, … , Thomas Gardella, Michael Mannstadt
Kelly L. Roszko, … , Thomas Gardella, Michael Mannstadt
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e91079. https://doi.org/10.1172/jci.insight.91079.
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Research Article Endocrinology

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

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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.

Authors

Kelly L. Roszko, Ruiye Bi, Caroline M. Gorvin, Hans Bräuner-Osborne, Xiao-Feng Xiong, Asuka Inoue, Rajesh V. Thakker, Kristian Strømgaard, Thomas Gardella, Michael Mannstadt

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Figure 6

Calcium and parathyroid hormone (PTH) increased significantly after injection of the calcilytic in WT mice and mice with activating Gα11.

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Calcium and parathyroid hormone (PTH) increased significantly after inje...
(A–C) Biochemical parameters at baseline and 4 and 24 hours after bolus i.p. injection of the calcilytic NPS 2143 (Drug) at 28 mg/kg or vehicle (Veh) in 9-week-old GNA11WT/WT (n = 14 vehicle, n = 14 calcilytic), GNA11R60C/WT (n = 13 vehicle, n = 13 calcilytic), and GNA11R60C/R60C (n = 6 vehicle, n = 6 calcilytic) mice. (A–C) blood iCa2+, (D–F) serum PTH, (G–I) serum Pi. Data are shown as mean ± SD. (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, using Student’s t test).

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