Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism

Parathyroid hormone secretion is negatively regulated by a 7- transmembranedomain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized thatactivating mutations in this receptor might cause autosomal dominanthypoparathyroidism (ADHP). Consistent with this hypothesis, we identified,in two families with ADHP, heterozygous missense mutations in theCa(2+)-sensing receptor gene that cosegregated with the disorder. None of50 normal controls had either mutation. We also identified a de novo,missense Ca(2+)-sensing receptor mutation in a child with severe sporadichypoparathyroidism. The amino acid substitution in one ADHP family affectedthe N-terminal, extracellular domain of the receptor. The other mutationsinvolved the transmembrane region. Unlike patients with acquiredhypoparathyroidism, patients with these mutations had hypercalciuria evenat low serum calcium concentrations. Their greater hypercalciuriapresumably reflected activation of Ca(2+)-sensing receptors in kidneycells, where the receptor negatively regulates calcium reabsorption. Thisaugmented hypercalciuria increases the risk of renal complications and thushas implications for the choice of therapy.