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  • The EMBO Journal (2003) 22, 5422 - 5434
  • doi:10.1093/emboj/cdg519

Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold

Thomas Boettger1,2, Marco B. Rust1, Hannes Maier3, Thomas Seidenbecher4, Michaela Schweizer1, Damien J. Keating1, Jörg Faulhaber5, Heimo Ehmke5, Carsten Pfeffer1, Olaf Scheel1, Beate Lemcke6, Jürgen Horst6, Rudolf Leuwer3, Hans-Christian Pape4, Harald Völkl7, Christian A. Hübner1,8 and Thomas J. Jentsch1

  1. Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20251 Hamburg, Germany
  2. Present address: Martin-Luther-Universität Halle-Wittenberg, Zentrum für medizinische Grundlagenforschung, Weinbergweg 22, D-06120 Halle, Germany
  3. HNO Klinik, Universitätsklinikum Eppendorf, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany
  4. Institut für Physiologie, Medizinische Fakultät, Otto-von-Guericke-Universität Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany
  5. Institut für Physiologie, Universitätsklinikum Eppendorf, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany
  6. Institut für Humangenetik, Universität Münster, Vesaliusweg 12–14, D-48149 Münster, Germany
  7. Institut für Physiologie der Universität Innsbruck, Fritz-Pregl-Strasse 3, A-6010 Innsbruck, Austria
  8. Institut für Humangenetik, Universitätsklinikum Eppendorf, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany

Correspondence to:

Thomas J. Jentsch, E-mail: Jentsch@zmnh.uni-hamburg.de

Received 5 February 2003; Accepted 18 August 2003; Revised 14 August 2003

K-Cl co-transporters are encoded by four homologous genes and may have roles in transepithelial transport and in the regulation of cell volume and cytoplasmic chloride. KCC3, an isoform mutated in the human Anderman syndrome, is expressed in brain, epithelia and other tissues. To investigate the physiological functions of KCC3, we disrupted its gene in mice. This severely impaired cell volume regulation as assessed in renal tubules and neurons, and moderately raised intraneuronal Cl- concentration. Kcc3-/- mice showed severe motor abnormalities correlating with a progressive neurodegeneration in the peripheral and CNS. Although no spontaneous seizures were observed, Kcc3-/- mice displayed reduced seizure threshold and spike-wave complexes on electrocorticograms. These resembled EEG abnormalities in patients with Anderman syndrome. Kcc3-/- mice also displayed arterial hypertension and a slowly progressive deafness. KCC3 was expressed in many, but not all cells of the inner ear K+ recycling pathway. These cells slowly degenerated, as did sensory hair cells. The present mouse model has revealed important cellular and systemic functions of KCC3 and is highly relevant for Anderman syndrome.

  • Keywords:

    • ACCPN,
    • blood pressure,
    • KCC4,
    • regulatory volume decrease,
    • SlC12A6