A Syndrome of Hypocalciuric Hypercalcemia Caused by Autoantibodies Directed at the Calcium-Sensing Receptor

Abstract

Antibodies to cell surface receptors can cause endocrine dysfunction by mimicking or blocking the actions of their respective hormones. We sought patients with autoantibodies to the extracellular calcium (Ca(2+)(o))-sensing receptor (CaR), which sets the normal level of blood calcium, that mimic the genetic disorder, familial hypocalciuric hypercalcemia, caused by heterozygous inactivating mutations of the CaR. Four individuals from two kindreds were identified with PTH-dependent hypercalcemia, who had other autoimmune manifestations: one with sprue and antigliadin and antiendomyseal antibodies and three with antithyroid antibodies. Three of the patients also had relative or absolute hypocalciuria. The patients' sera contained antibodies that reacted with the cell surface of bovine parathyroid cells in a manner similar to an authentic polyclonal anti-CaR antibody, stained bands on Western analysis of sizes similar to those labeled by the anti-CaR antiserum, and reacted with several synthetic peptides derived from sequences within the CaR's extracellular amino terminus. The patients' sera also stimulated PTH release from dispersed human parathyroid cells compared with the effect of sera from normocalcemic control subjects. This stimulation could be blocked by preabsorbing serum with membranes from CaR-transfected, but not nontransfected, human embryonic kidney (HEK293) cells. Finally, in two of the patients, antibodies affinity-purified using a synthetic peptide from within the CaR's extracellular domain inhibited high Ca(2+)(o)-stimulated, CaR-mediated accumulation of inositol phosphates and activation of mitogen-activated protein kinase in CaR-transfected HEK293 cells. DNA sequencing revealed no mutations within the index patients' CaR genes in the two families. Therefore, a biochemical phenotype of PTH-dependent hypercalcemia resembling that caused by heterozygous inactivating mutations of the CaR in familial hypocalciuric hypercalcemia can be observed in patients with antibodies to the CaR's extracellular domain that stimulate PTH release, probably by inhibiting activation of the CaR by Ca(2+)(o). Autoimmune hypocalciuric hypercalcemic is an acquired disorder of Ca(2+)(o) sensing that should be differentiated from that caused by inactivating mutations of the CaR.

Physiology and pathophysiology of the calcium-sensing receptor in the kidney

“…These patients have PTHdependent hypercalcemia in the setting of other autoimmune conditions (e.g., Hashimoto thyroiditis) and, in most reported cases, exhibit hypocalciuria; all harbor anti-CaSR antibodies detected by various immunologic tests (e.g., ELISA, Western blot, etc.). In one study of four AHH patients, the anti-CaSR antibodies blunted CaSR-mediated activation of PLC and MAPK activity at physiological levels of Ca o 2ϩ (83). As expected for an inactivating antibody, PTH release from parathyroid cells incubated with patient sera was higher at any given level of Ca 2ϩ relative to cells incubated with control sera.…”

“…About a dozen patients have been described with inactivating (83,98,116) or activating (79,82) autoantibodies directed at the CaSR. Inactivating antibodies cause autoimmune hypocalciuric hypercalcemia (AHH).…”

“…In another AHH patient, the anti-CaSR antibodies unexpectedly potentiated high Ca o 2ϩ -evoked PLC activity (i.e., had CaSR activating properties) but blunted MAPK activation (98), suggesting differential coupling of the antibody-bound receptor to these two signaling pathways. In some of the cases described to date, the autoantibodies likely interact with the CaSR in the kidney, thereby producing relative or absolute hypocalciuria despite hypercalcemia, as in FHH (83,116). Thus inactivating antibodies can produce a clinical and biochemical picture similar to that caused by inactivating mutations in FHH.…”

Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism

“…However, such a phenomenon by itself would not bring about the parathyroid gland atrophy and lymphocytic infiltration that have been observed and reported at autopsy in a few patients with idiopathic hypoparathyroidism (4). While the above facts argue against a primary role and any functional significance of the CaSRAb among patients with idiopathic hypoparathyroidism, there is a recent report of CaSR blocking autoantibodies described in patients with a syndrome resembling familial hypocalciuric hypercalcemia (36). However, in order to reveal the pathogenetic mechanism(s) at work, further studies need to be done in vitro to examine the possible role of the CaSR autoantibody in altering the normal functioning of the G-protein-mediated intracellular signalling pathways used by this receptor, as well as an analysis of the Th1 and Th2 cytokine profiles among patients with idiopathic hypoparathyroidism.…”

Muscle function and quality of life are not impaired in familial hypocalciuric hypercalcemia: a cross-sectional study on physiological effects of inactivating variants in the calcium-sensing receptor gene (CASR)

“…Recently, similar phenotypes have been shown to be attributable to mutations in the G protein alpha 11 (Ga11(GNA11)) gene (FHH type 2) and adaptor protein 2 sigma 1 (AP2S1) gene (FHH type 3) with loci placed on chromosomes 19p and 19q respectively (10). In rare cases, antibodies to the CaSR may also cause a FHH-like phenotype (11,12).…”