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A Novel Activating Mutation in Calcium-Sensing Receptor Gene Associated with a Family of Autosomal Dominant Hypocalcemia¹

Third Department of Medicine, Teikyo University School of Medicine (R.O., K.T.), 3426–3 Anesaki, Ichihara, Chiba 299-0111; Second Department of Research (M.N., M.A.), Department of Metabolism and Endocrinology (M.A., J.M., Y.To.), Kanto-Teishin Hospital, 5–9-22 Higashi-Gotanda, Shinagawa, Tokyo 141-0022; and Fourth Department of Internal Medicine, University of Tokyo School of Medicine (N.C., Y.Ta., T.F., S. F), 3–8-6 Mejirodai, Bunkyo, Tokyo 112-0015, Japan

Address all correspondence and requests for reprints to: Ryo Okazaki, M.D., Third Department of Medicine, Teikyo University School of Medicine, 3426–3 Anesaki, Ichihara 299-0111, Japan. E-mail: rokazaki{at}med.teikyo-u.ac.jp

Autosomal dominant hypocalcemia (ADH), caused by activating mutations of the calcium-sensing receptor (CaSR), is characterized by hypocalcemia with an inappropriately low concentration of PTH. Among 11 missense mutations of CaSR reported to date in patients with ADH or sporadic hypocalcemia, functional properties of 8 mutant CaSRs were characterized. Here, we describe a novel mutation of CaSR and its functional property in a family with ADH. The 41-yr-old male proband had asymptomatic hypocalcemia with a history of recurrent nephrolithiasis. His father had asymptomatic hypocalcemia, but his mother was normocalcemic. PCR-single strand conformation polymorphism and sequencing revealed that both the proband and the father had a novel heterozygous mutation in CaSR gene that causes lysine to asparagine substitution at codon 47 (K47N), which is in the extracellular domain of CaSR, like 6 of 11 known activating mutations. Using HEK293 cells transfected with wild-type or K47N CaSR complementary DNA, the intracellular Ca²⁺ concentration was assessed in response to changes in the extracellular Ca²⁺ concentration. The EC₅₀ of the mutant CaSR for the extracellular Ca²⁺ concentration was 2.2 mmol/L and was significantly lower than that of wild-type (3.7 mmol/L). These results confirm that this mutation is responsible for ADH in this family. The fact that several inactivating mutations in familial hypocalciuric hypercalcemia occur in amino acid around K47 suggests the importance of the N-terminal portion of the receptor in extracellular Ca sensing.

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