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

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1Third Department of Medicine, Teikyo University School of Medicine (R.O., K.T.), 3426–3 Anesaki, Ichihara, Chiba 299-0111;

*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.

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4Fourth 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

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2Second Department of Research (M.N., M.A.), Shinagawa, Tokyo 141-0022;

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4Fourth 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

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2Second Department of Research (M.N., M.A.), Shinagawa, Tokyo 141-0022;

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3Department of Metabolism and Endocrinology (M.A., J.M., Y.To.), Kanto-Teishin Hospital, 5–9-22 Higashi-Gotanda, Shinagawa, Tokyo 141-0022;

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4Fourth 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

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2Second Department of Research (M.N., M.A.), Shinagawa, Tokyo 141-0022;

3Department of Metabolism and Endocrinology (M.A., J.M., Y.To.), Kanto-Teishin Hospital, 5–9-22 Higashi-Gotanda, Shinagawa, Tokyo 141-0022;

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3Department of Metabolism and Endocrinology (M.A., J.M., Y.To.), Kanto-Teishin Hospital, 5–9-22 Higashi-Gotanda, Shinagawa, Tokyo 141-0022;

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1Third Department of Medicine, Teikyo University School of Medicine (R.O., K.T.), 3426–3 Anesaki, Ichihara, Chiba 299-0111;

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Revision received:

11 September 1998

Accepted:

22 September 1998

Published:

01 January 1999

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Ryo Okazaki, Noriko Chikatsu, Masami Nakatsu, Yasuhiro Takeuchi, Miho Ajima, Junko Miki, Toshiro Fujita, Masanobu Arai, Yasuo Totsuka, Koshi Tanaka, Seiji Fukumoto, A Novel Activating Mutation in Calcium-Sensing Receptor Gene Associated with a Family of Autosomal Dominant Hypocalcemia, The Journal of Clinical Endocrinology & Metabolism, Volume 84, Issue 1, 1 January 1999, Pages 363–366, https://doi.org/10.1210/jcem.84.1.5385
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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.

Copyright © 1999 by The Endocrine Society

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