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A Large Homozygous or Heterozygous In-Frame Deletion within the Calcium-Sensing Receptor’s Carboxylterminal Cytoplasmic Tail That Causes Autosomal Dominant Hypocalcemia¹

Service de Pédiatrie 2 (A.L., J.B.), Centre Hospitalier Universitaire, 87042 Limoges, France; Centre National de la Recherche Scientifique Unité Proper de Recherche 1524 (M.G., C.S.), Hôpital Saint Vincent de Paul, 75014 Paris, France; Endocrine-Hypertension Division (M.B., Z.Z., E.M.B.), Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115; Unité de Biologie Moléculaire (J.-P.L., M.-L.K.), Service de Biochimie Médicale, AP-HP, Hôpital Pitié-Salpétrière, 75013 Paris, France; and Service de Biochimie (A.L., M.R.), Faculté de Médecine, 87025 Limoges, France

Address correspondence and requests for reprints to: Dr. Anne Lienhardt, Service de Pédiatrie 2, Centre Hospitalier Universitaire Dupuytren, 2 avenue Martin Luther King, 87042 Limoges cedex, France. E-mail: anne.lienhardt{at}unilim.fr

Autosomal dominant hypocalcemia (ADH) can result from heterozygous missense activating mutations of the calcium-sensing receptor (CaSR) gene, a G-protein-coupled receptor playing key roles in mineral ion metabolism. We now describe an ADH kindred of three generations caused by a novel CaSR mutation, a large in-frame deletion of 181 amino acids within its carboxylterminal-tail from S895 to V1075. Interestingly, the affected grandfather is homozygous for the deletion but no more severely affected than heterozygous affected individuals. Functional properties of mutant and wild-type (WT) CaSRs were studied in transiently transfected, fura-2-loaded human embryonic kidney (HEK293) cells. The mutant receptor exhibited a gain-of-function, but there was no difference between cells transfected with mutant complementary DNA alone or cotransfected with mutant and WT complementary DNAs, consistent with the similar phenotypes of heterozygous and homozygous family members. Therefore, this activating deletion may exert a dominant positive effect on the WT CaSR. The mutant receptor’s cell surface expression was greater than that of the WT CaSR, potentially contributing to its gain-of-function. This novel mutation in the CaSR gene provides the first known examples of a large naturally occurring deletion within a G-protein-coupled receptor’s carboxylterminal-tail and of a homozygous, affected individual with ADH.

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