Functional activities of mutant calcium-sensing receptors determine clinical presentations in patients with autosomal dominant hypocalcemia

Abstract

Objective: Autosomal dominant hypocalcemia (ADH) is a congenital isolated hypoparathyroidism caused by activating mutations in the calcium-sensing receptor (CASR) gene. The clinical features ofADHare heterogeneous;somepatients are asymptomatic,andothersshowsevere hypocalcemia with Bartter's syndrome. We therefore recruited 12 patients with ADH to clarify the determinants of their clinical presentation. Design and Methods:Westudied two sporadic and 10 familial cases of ADH. Serum concentrations of calcium, intact PTH, and magnesium (Mg2+) were measured in each patient. Fractional excretion of Mg (FEMg) was calculated in spot urine samples. A nuclear factor of activated T cells luciferase assay was used to analyze the responsiveness of each mutant CaSR to extracellular Ca2+. Results: Genomic analysis revealed five known activating mutations and a novel mutation, E481K, in the CASR. Patients with the A843E, C131W, or F788C mutation showed hypomagnesemia with elevated FEMg. Intact PTH in these patients was consistently near the detection limit. In contrast, patients with the P221L, K47N, or E481K mutation exhibited normalMg2+ levels. In these patients, intact PTH increased in response to low calcium, and their maximum intact PTH exceeded the lower limit of the reference range. Functional analysis showed an association between the disease severity and the in vitro activity of the mutant CaSR. Conclusions: The functional activity of mutant CaSR determines the serum Mg 2- level, renal Mg2- handling, and intact PTH in patients with ADH. The presence of hypomagnesemia with elevated FEMg may indicate the diagnosis of ADH among patients with PTH-deficient hypoparathyroidism. Copyright © 2014 by the Endocrine Society.