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.
Highlights
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder of extracellular calcium (Ca2+o) homeostasis characterized by lifelong elevations in serum calcium concentrations in association with normal or mildly elevated serum parathyroid hormone (PTH) concentrations and normal or low fractional excretion of calcium (1–4)
Our studies have established a mouse model with a germline loss-offunction G-protein subunit α11 (Gα11) mutation that is representative for familial hypocalciuric hypercalcemia type 2 (FHH2) in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH
FHH3 (OMIM 600740) is caused by heterozygous loss-of-function mutations of the adaptor protein-2 σ subunit (AP2σ), encoded by the AP2S1 gene on chromosome 19q13.3, which is involved in the clathrin-mediated endocytosis of cell-surface proteins such as the calcium-sensing receptor (CaSR) (4, 11)
Summary
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder of extracellular calcium (Ca2+o) homeostasis characterized by lifelong elevations in serum calcium concentrations in association with normal or mildly elevated serum parathyroid hormone (PTH) concentrations and normal or low fractional excretion of calcium (1–4). The CaSR is a widely expressed family C GPCR that regulates PTH secretion and urinary calcium excretion by transducing elevations in [Ca2+]o into multiple intracellular signaling cascades in the parathyroid glands and kidneys, respectively (5, 6). FHH1 (OMIM 145980) is caused by heterozygous loss-of-function mutations of the CaSR, which is encoded by the CASR gene on chromosome 3q21.1 (1). FHH2 (OMIM 145981) is due to heterozygous loss-of-function mutations of G-protein subunit α11 (Gα11), which is encoded by the GNA11 gene on chromosome 19p13.3, and to date, 3 FHH2-associated mutations have been reported, comprising 2 missense mutations, Thr54Met and Leu135Gln, and an in-frame isoleucine deletion at codon 200 (Ile200del) (3, 10). FHH3 (OMIM 600740) is caused by heterozygous loss-of-function mutations of the adaptor protein-2 σ subunit (AP2σ), encoded by the AP2S1 gene on chromosome 19q13.3, which is involved in the clathrin-mediated endocytosis of cell-surface proteins such as the CaSR (4, 11)
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