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Autosomal Dominant Hypocalcemia: A Novel Activating Mutation (E604K) in the Cysteine-Rich Domain of the Calcium-Sensing Receptor

Department of Medicine (Y.M.T.), Townsville Hospital, Townsville, Queensland 4810; Department of Diabetes and Endocrinology (J.C., J.B.P.), Princess Alexandra Hospital, Woolloongabba, Queensland 4102; and School of Molecular and Microbial Biosciences (A.H.F., H.-C.M., N.L., L.B.H., A.D.C.), University of Sydney, Sydney, New South Wales 2006, Australia

Address all correspondence and requests for reprints to: A/Prof. Arthur D. Conigrave, Department of Biochemistry (G08), University of Sydney, NSW 2006, Australia. E-mail: a.conigrave{at}mmb.usyd.edu.au.

We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A; GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven individuals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca²⁺ on both intracellular Ca²⁺ mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca²⁺ concentrations.

A.D.C.’s research is supported by the National Health and Medical Research Council of Australia.

Abbreviations: ADH, Autosomal dominant hypocalcemia; CaR, calcium-sensing receptor; Cys-rich, cysteine-rich; PI-PLC, phosphoinositide-specific phospholipase C; VFT, Venus Fly-Trap.

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