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A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism

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Abstract

Gain-of-function mutations of the extracellular calcium (Ca2+e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation (F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca2+e-evoked changes in intracellular Ca2+ revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor. Conclusion:the F821L mutation is therefore a novel gain-of-function mutation which can cause severe hypoparathyroidism. Thiazide diuretics lowered urinary calcium excretion of the patient treated with calcium supplementation and 1α-hydroxyvitamin D3.

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Abbreviations

Ca2+e:

extracellular calcium

Ca2+i:

intracellular calcium

CaR :

calcium-sensing receptor

PTH :

parathyroid hormone

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Authors and Affiliations

  1. Department of Paediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, 390-8621, Matsumoto, Japan

    Masaaki Shiohara

  2. National Nagano Hospital, Ueda, Japan

    Tetsuo Mori

  3. Harvard Medical School, Cambridge, Massachusetts, USA

    Bai Mei & Edward M. Brown

  4. National Chiba Hospital and Chiba University Graduate School of Medicine, Chiba, Japan

    Tomoyuki Watanabe & Toshiyuki Yasuda

Authors
  1. Masaaki Shiohara
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  2. Tetsuo Mori
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  3. Bai Mei
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  4. Edward M. Brown
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  5. Tomoyuki Watanabe
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  6. Toshiyuki Yasuda
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Correspondence to Masaaki Shiohara.

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Shiohara, M., Mori, T., Mei, B. et al. A novel gain-of-function mutation (F821L) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism. Eur J Pediatr 163, 94–98 (2004). https://doi.org/10.1007/s00431-003-1331-7

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  • DOI: https://doi.org/10.1007/s00431-003-1331-7

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