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

Endocrine-Hypertension Division and Membrane Biology Program, and Department of Surgery (F.D.M.), Brigham and Women’s Hospital, and Endocrine Division, Beth Israel Deaconess Medical Center (J.G.), Harvard Medical School (O.K., K.D.M., M.D., J.G., R.B., I.K., E.M.B.), Boston, Massachusetts 02115; Calcium Laboratory, Royal Victoria Hospital, Department of Medicine, McGill University (G.N.H.), Montreal, Canada; Scantibodies Laboratories (P.G., T.L.C.), Santee, California 92071; and Endocrine Division, Department of Medicine, Yale University School of Medicine (J.W.), New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Edward M. Brown, M.D., Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, Massachusetts 02115. E-mail: embrown{at}rics bwh.harvard.edu.

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 (Ca²⁺_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 Ca²⁺_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 Ca²⁺_o. Autoimmune hypocalciuric hypercalcemic is an acquired disorder of Ca²⁺_o sensing that should be differentiated from that caused by inactivating mutations of the CaR.

E.M.B. and J.W. contributed equally to this work.

Abbreviations: Ca²⁺_o, Extracellular calcium; CaR, calcium-sensing receptor; ERK, extracellular signal-regulated kinase; FHH, familial hypocalciuric hypercalcemia; MAPK, mitogen-activated protein kinase; PHPT, primary hyperparathyroidism; TCA, trichloroacetic acid.

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