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A Family of Autosomal Dominant Hypocalcemia with a Positive Correlation between Serum Calcium and Magnesium: Identification of a Novel Gain of Function Mutation (Ser⁸²⁰Phe) in the Calcium-Sensing Receptor

Growth Factor Division, National Cancer Center Research Institute (T.N., T.T., K.Y.), Tokyo 104-0045, Japan; Third Department of Internal Medicine (T.M., R.K., Y.T., N.N.) and Department of General Medicine (T.A.), National Defense Medical College, Saitama 359-8513, University of Tokyo Branch Hospital (N.C., S.F.), Tokyo 112-8868, Japan; Department of Internal Medicine, Self-Defense Forces Central Hospital (T.N., H.T., N.T., H.Y.), Tokyo 154-8532, Japan; and Department of Health and Nutrition, School of Health Sciences, Niigata University of Health and Welfare, Niigata 950-3198 (M.Y.), Japan

Address all correspondence and requests for reprints to: Michiko Yamamoto, M.D., Department of Health Sciences, Niigata University of Health and Welfare, 1398 Shimami-cho, Niigata 950-3198, Japan. E-mail: . yamamoto{at}nuhw.ac.jp

Abstract

To date about 20 activating mutations in the calcium-sensing receptor (CaR) gene have been identified to cause autosomal dominant hypocalcemia (ADH) or sporadic hypoparathyroidism. We report a novel activating mutation in the CaR gene in a Japanese family with ADH. The proband, a 15-yr-old boy, and 5 other patients in 3 generations were asymptomatic, except for the proband’s grandmother who had a history of seizures. They showed mild hypocalcemia (1.68–1.98 mmol/liter) with normal urinary calcium excretion and low normal serum PTH levels. Their serum magnesium concentrations were below normal in 3 adults and within the normal range in 3 teenagers. There was a significant positive correlation (r = 0.90; P < 0.05) between the serum calcium and magnesium concentrations of 6 affected members. Nucleotide sequencing revealed that the proband had a known polymorphism (Gly⁹⁹⁰Arg) and a novel heterozygous mutation substituting phenylalanine for serine at codon 820 (Ser⁸²⁰Phe) in the sixth transmembrane helix of the CaR. In other family members, the Ser⁸²⁰Phe mutation cosegregated with hypocalcemia. The mutation was not detected in 50 control subjects. The Gly⁹⁹⁰Arg polymorphism was observed in 8 of 9 family members with or without hypocalcemia and in 36 of 50 controls. The sensitivity of the Ser⁸²⁰Phe mutant CaR to calcium was assessed using transiently transfected HEK293 cells and measuring the increases in intracellular Ca²⁺ concentrations in response to the changes in extracellular Ca²⁺. The concentration-response curve of the mutant receptor was left-shifted, and its EC₅₀ (2.5 mM) was significantly (P < 0.05) lower than that of the wild-type CaR (3.3 mM). We conclude that the Ser⁸²⁰Phe mutation in the CaR caused ADH in this family. The positive correlation between serum calcium and magnesium levels observed in this family may support the concept that renal CaR acts as a magnesium sensor as well as a calcium sensor.

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