Bockenhauer, Detlef and Feather, Sally and Stanescu, Horia C. and Bandulik, Sascha and Zdebik, Anselm A. and Reichold, Markus and Tobin, Jonathan and Lieberer, Evelyn and Sterner, Christina and Landoure, Guida and Arora, Ruchi and Sirimanna, Tony and Thompson, Dorothy and Cross, J. Helen and van't Hoff, William and Al Masri, Omar and Tullus, Kjell and Yeung, Stella and Anikster, Yair and Klootwijk, Enriko and Hubank, Mike and Dillon, Michael J. and Heitzmann, Dirk and Arcos-Burgos, Mauricio and Knepper, Mark A. and Dobbie, Angus and Gahl, William A. and Warth, Richard and Sheridan, Eamonn and Kleta, Robert (2009) Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations. NEW ENGLAND JOURNAL OF MEDICINE, 360 (19). pp. 1960-1970. ISSN 0028-4793, 1533-4406
Full text not available from this repository. (Request a copy)Abstract
Background: 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). Methods: 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. Results: 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. Conclusions: 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. N Engl J Med 2009;360:1960-70.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DISTAL CONVOLUTED TUBULE; WIDE LINKAGE ANALYSIS; NA-CL COTRANSPORTER; BARTTERS-SYNDROME; K+ CHANNEL; POTASSIUM CHANNEL; BLOOD-PRESSURE; HYPOKALEMIC ALKALOSIS; BASOLATERAL MEMBRANE; KNOCK-OUT; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Sep 2020 09:49 |
| Last Modified: | 14 Sep 2020 09:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28983 |
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