title: 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.
authors.affiliation: Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Kifor
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Miriam
authors.initials: M
authors.lastname: Delaney
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Garber
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.forename: Robert
authors.initials: R
authors.lastname: Butters
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Cantor
authors.forename: Imre
authors.initials: I
authors.lastname: Kifor
authors.forename: Edward M
authors.initials: EM
authors.lastname: Brown
authors.forename: John
authors.initials: J
authors.lastname: Wysolmerski
mesh_terms: D000328:Adult; D001323:Autoantibodies / Q000097:blood / Q000276:immunology* / Q000502:physiology; D001790:Blood Physiological Phenomena; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology / Q000652:urine*; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D007136:Immunoglobulins / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010280:Parathyroid Glands / Q000276:immunology / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D010375:Pedigree; D010446:Peptide Fragments / Q000276:immunology; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D013577:Syndrome
chemical_list: D001323:Autoantibodies; D007136:Immunoglobulins; D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium