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Sporadic Hypoparathyroidism Caused by de Novo Gain- of-Function Mutations of the Ca²⁺-Sensing Receptor¹

Developmental Endocrinology Branch, National Institute of Child Health and Human Development (F.D.L., E.E.M., K.K.W., J.B.), and Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease (K.R., G.-F.F., A.M.S.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Francesco De Luca, M.D., Building 10, Room 10N262, National Institutes of Health, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: delucaF{at}cc1.nichd.nih.gov

Activating mutations of the Ca²⁺-sensing receptor (CaR) gene have been identified in families with autosomal dominant hypoparathyroidism and in one patient with sporadic hypoparathyroidism. Here, we describe two additional patients with sporadic hypoparathyroidism. One patient presented with mild symptoms at age 18 yr; the other was severely symptomatic from infancy. A heterozygous missense mutation was identified in each patient. One mutation (L773R) involved the fifth transmembrane domain of the CaR, the other (N118K) affected the amino-terminal, extracellular domain. In both cases, the probands’ parents lacked the mutation, indicating that the mutations arose de novo. In expression studies the mutations shifted the concentration-response curve to the left and increased maximal activity. We conclude that 1) sporadic hypoparathyroidism can be caused by de novo gain-of-function mutations of the CaR; 2) the phenotype can vary from mild to life-threatening hypocalcemia; 3) gain-of-function mutations can involve not only extracellular regions, as previously reported, but also transmembrane domains of the CaR; and 4) the mechanism of activation can involve both increased receptor sensitivity to Ca²⁺ and increased maximal signal transduction.

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