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Previous Volume 360:1960-1970 May 7, 2009 Number 19 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Bleich, M. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

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.

Source Information

From the Great Ormond Street Hospital–University College London, London (D.B., H.C.S., A.A.Z., J.T., G.L., R.A., T.S., D.T., J.H.C., W.H., K.T., E.K., M.H., M.J.D., R.K.); Leeds and Bradford Teaching Hospitals–University of Leeds, Leeds, United Kingdom (S.F., S.Y., A.D., E.S.); National Institutes of Health, Bethesda, MD (H.C.S., G.L., Y.A., E.K., M.A.-B., M.A.K., W.A.G., R.K.); Institute of Physiology, University of Regensburg, Regensburg, Germany (S.B., M.R., E.L., C.S., D.H., R.W.); the Department of Neurology, University of Bamako, Bamako, Mali (G.L.); Sheikh Khalifa Medical City, Abu Dhabi, United Arab Emirates (O.A.M.); Sheba Medical Center, Tel-Hashomer, Israel (Y.A.); and University of Miami, Miami (M.A.-B.).

Drs. Bockenhauer, Feather, Stanescu, Warth, Sheridan, and Kleta contributed equally to this article.

Address reprint requests to Dr. Kleta at the Center for Nephrology, University College London, Royal Free Hospital, Rowland Hill St., London NW3 2PF, United Kingdom, or at r.kleta{at}ucl.ac.uk.

Full Text of this Article

Related Letters:

The EAST Syndrome and KCNJ10 Mutations
Shi M., Zhao G., Bockenhauer D., Stanescu H. C., Kleta R.
Extract | Full Text | PDF  
N Engl J Med 2009; 361:630-631, Aug 6, 2009. Correspondence

This article has been cited by other articles:

• Zdebik, A. A., Wangemann, P., Jentsch, T. J. (2009). Potassium Ion Movement in the Inner Ear: Insights from Genetic Disease and Mouse Models. Physiology 24: 307-316 [Abstract] [Full Text]  
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