Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation.

摘要: 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 low urinary calcium excretion. A mouse model that would facilitate investigations vivo role Gα11 evaluation calcimimetic drugs, are CaSR allosteric activators, not available. We therefore screened DNA from > 10,000 mice treated with chemical mutagen N-ethyl-N-nitrosourea (ENU) GNA11 identified variant, Asp195Gly (D195G), downregulated CaSR-mediated intracellular vitro, consistent it being loss-of-function mutation. Treatment cinacalcet rectified these responses. In studies showed mutant heterozygous (Gna11+/195G) homozygous (Gna11195G/195G) to be hypercalcemic increased plasma PTH concentrations Cinacalcet (30mg/kg orally) significantly reduced albumin-adjusted Gna11+/195G Gna11195G/195G mice. Thus, our have established germline mutation representative humans demonstrated can correct associated abnormalities PTH.