A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor
Simon H.S. Pearce, M.R.C.P., Catherine Williamson, M.R.C.P., Olga Kifor, M.D., Mei Bai, Ph.D., Malcolm G. Coulthard, F.R.C.P., Michael Davies, M.D., Nicholas Lewis-Barned, F.R.A.C.P., David McCredie, M.D., Harley Powell, F.R.A.C.P., Pat Kendall-Taylor, M.D., Edward M. Brown, M.D., and Rajesh V. Thakker, M.D.
Background The calcium-sensing receptor regulates the secretionof parathyroid hormone in response to changes in extracellularcalcium concentrations, and mutations that result in a lossof function of the receptor are associated with familial hypocalciurichypercalcemia. Mutations involving a gain of function have beenassociated with hypocalcemia in two kindreds. We examined thepossibility that the latter type of mutation may result in aphenotype of familial hypocalcemia with hypercalciuria.
Methods We studied six kindreds given a diagnosis of autosomaldominant hypoparathyroidism on the basis of their hypocalcemiaand normal serum parathyroid hormone concentrations, a combinationthat suggested a defect of the calcium-sensing receptor. Thehypocalcemia was associated with hypercalciuria, and treatmentwith vitamin D resulted in increased hypercalciuria, nephrocalcinosis,and renal impairment. Mutations in the calcium-sensing–receptorgene were identified by DNA-sequence analysis and expressedin human embryonic kidney cells (HEK-293).
Results Five heterozygous missense mutations (Asn118Lys, Phe128Leu,Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellulardomain of the calcium-sensing–receptor gene and shownto cosegregate with the disease. Analysis of the functionalexpression of three of the mutant receptors in HEK-293 cellsdemonstrated shifts in the dose–response curves so thatthe extracellular calcium concentrations needed to produce half-maximalincreases in total inositol phosphate in the cells were significantly(P = 0.02 to P<0.001) lower than those required for the wild-typereceptor.
Conclusions Gain-of-function mutations in the calcium-sensingreceptor are associated with a familial syndrome of hypocalcemiawith hypercalciuria that needs to be distinguished from hypoparathyroidism.
Source Information
From the Medical Research Council Molecular Endocrinology Group, Royal Postgraduate Medical School, London (S.H.S.P., C.W., R.V.T.); the Endocrine–Hypertension Division, Brigham and Women's Hospital, Boston (S.H.S.P., O.K., M.B., E.M.B.); the Paediatric (M.G.C.) and Endocrine (P.K.-T.) Units, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; the Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom (M.D.); the Department of Medicine, University of Otago, Dunedin, New Zealand (N.L.-B.); and the Royal Children's Hospital, Melbourne, Victoria, Australia (D.M., H.P.).
Address reprint requests to Dr. Thakker at the MRC Molecular Endocrinology Group, MRC Clinical Sciences Centre, Collier Bldg., Royal Postgraduate Medical School, Hammersmith Hospital, DuCane Rd., London W12 0NN, United Kingdom.
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