Association between activating mutations of calcium-sensing receptor and Bartterʹs syndrome

Bartterʹs syndrome is a heterogeneous disorder characterised by deficient renal reabsorption of sodium and chloride, and hypokalaemic metabolic alkalosis with hyper-reninaemia and hyperaldosteronaemia. Mutations in several ion transporters and channels have been associated with the pathogenesis of Bartterʹs syndrome. We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartterʹs syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients. Activation of this calcium sensing receptor inhibits the activity of a renal outer-medullary potassium channel that is mutated in type 2 Bartterʹs syndrome. We therefore suggest that some activating mutations of CASR could provide new mechanisms for the development of Bartterʹs syndrome.