A Familial Syndrome of Hypocalcemia with Hypercalciuria Due to Mutations in the Calcium-Sensing Receptor

Pearce, Simon H.S.
Williamson, Catherine
Kifor, Olga
Bai, Mei
Coulthard, Malcolm G.
Davies, Michael
Lewis-Barned, Nicholas
McCredie, David
Powell, Harley
Kendall-Taylor, Pat
Brown, Edward M.
Thakker, Rajesh V.

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.

New England Journal of Medicine 335(15):p 1115-1122, October 10, 1996. | DOI: 10.1056/NEJM199610103351505

Background

The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria.

Methods

We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293).

Results

Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P = 0.02 to P<0.001) lower than those required for the wild-type receptor.

Conclusions

Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism. (N Engl J Med 1996;335:1115-22.)