Introduction and Methods Five patients from two consanguineous families presented with epilepsy from infancy, severe ataxia, moderate sensorineural deafness, and a renal salt losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this new autosomal recessive disease termed EAST syndrome. Whole genome linkage analysis was performed in a family with four affected children and multiple consanguineous links. Newly identified mutations in the Kcnj10 potassium channel gene were evaluated using Xenopus oocytes. Localization and function were characterised in WT and KCNJ10 KO mice. Results Linkage analysis identified a single relevant locus on chromosome 1q23.2 with a LOD score of 4.98. This region contained Kcnj10, which encodes a potassium channel, also known as Kir 4.1, expressed in brain, inner ear, and the kidney. Sequencing of this gene revealed homozygous missense mutations in affected persons in both families. Mutant KCNJ10 showed significantly decreased potassium currents in Xenopus oocytes (R65P decreased to about 25%, while currents from G77R were not significantly different from water-injected oocytes, N>3, n>20). Kcnj10 KO mice became dehydrated and exhibited evidence of renal salt wasting. Immunohistochemistry revealed prominent expression in the distal tubule (n=3), explaining salt loss and changes in renal handling of divalent cations. Expression was confined to the basolateral membrane, where KCNJ10 may function in both generating the driving force for Cl- reabsorption through ClC-K/barttin channels and supplying K+ to the Na+/K+-ATPase, both affecting NaCl reabsorption through NCC. Discussion In conclusion, mutations in KCNJ10 cause epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate a major role for KCNJ10 in hearing, regulating excitability in the brain, renal salt handling and possibly blood pressure maintenance and its regulation in humans.