Referenced in: none

Automatically associated channels: Kir1.1 , Kir4.1

Title: Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.

Authors: Detlef Bockenhauer, Sally Feather, Horia C Stanescu, Sascha Bandulik, Anselm A Zdebik, Markus Reichold, Jonathan Tobin, Evelyn Lieberer, Christina Sterner, Guida Landoure, Ruchi Arora, Tony Sirimanna, Dorothy Thompson, J Helen Cross, William van't Hoff, Omar Al Masri, Kjell Tullus, Stella Yeung, Yair Anikster, Enriko Klootwijk, Mike Hubank, Michael J Dillon, Dirk Heitzmann, Mauricio Arcos-Burgos, Mark A Knepper, Angus Dobbie, William A Gahl, Richard Warth, Eamonn Sheridan, Robert Kleta

Journal, date & volume: N. Engl. J. Med., 2009 May 7 , 360, 1960-70

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19420365

Abstract
Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy).Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice.Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting.Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.