Ca²⁺-SENSING RECEPTOR MUTATIONS IN SPORADIC HYPOPARATHYROIDISM.• 507

Missense mutations of the Ca²⁺-sensing receptor (CSR) gene have been identified in 4 families with autosomal dominant hypoparathyroidism and in one child with sporadic hypoparathyroidism. To cause the phenotype, these mutations must activate the CSR, since the receptor negatively regulates parathyroid hormone (PTH) secretion. We showed previously that patients with CSR mutations, while hypocalcemic, manifested greater hypercalciuria than did patients with other causes of hypoparathyroidism, apparently because the CSR negatively regulates Ca²⁺ resorption from the glomerular filtrate. Thus, we hypothesized that this disproportionate hypercalciuria could be used to distinguish sporadic hypoparathyroidism due to de novo CSR mutations from hypoparathyroidism due to other causes. To test this hypothesis, we studied two unrelated female patients with no family history of hypoparathyroidism, both of whom had hypocalcemia, hyperphosphatemia, low serum PTH, and disproportionate hypercalciuria. Patient A presented with mild symptoms of hypocalcemia at age 18, whereas patient B was severely symptomatic from infancy. Polyacrylamide gel electrophoresis of PCR-amplified genomic DNA showed heteroduplex bands in exon 6 for patient A and in exon 2 for patient B. In patient A, direct sequencing of the PCR product identified a T2318G base-pair substitution encoding a Leu to Arg change at residue 773 of the fifth transmembrane domain. Patient B showed a C354A substitution encoding an Asn to Lys change at residue 118 in the N-terminal extracellular domain. Family studies suggested that both mutations arose de novo. We conclude that 1) mutations of the CSR gene cause sporadic as well as familial hypoparathyroidism, 2) phenotypic severity varies greatly depending on the specific mutation, and 3) levels of 24h Ca²⁺ excretion can identify hypoparathyroid patients with CSR gene mutations, which has implications for genetic counseling, prognosis, and therapy.