title: Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold.
abstract: 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.
authors.affiliation: Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20251 Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.forename: Marco B
authors.initials: MB
authors.lastname: Rust
authors.forename: Hannes
authors.initials: H
authors.lastname: Maier
authors.forename: Thomas
authors.initials: T
authors.lastname: Seidenbecher
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Damien J
authors.initials: DJ
authors.lastname: Keating
authors.forename: Jörg
authors.initials: J
authors.lastname: Faulhaber
authors.forename: Heimo
authors.initials: H
authors.lastname: Ehmke
authors.forename: Carsten
authors.initials: C
authors.lastname: Pfeffer
authors.forename: Olaf
authors.initials: O
authors.lastname: Scheel
authors.forename: Beate
authors.initials: B
authors.lastname: Lemcke
authors.forename: Jürgen
authors.initials: J
authors.lastname: Horst
authors.forename: Rudolf
authors.initials: R
authors.lastname: Leuwer
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Pape
authors.forename: Harald
authors.initials: H
authors.lastname: Völkl
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D000818:Animals; D048429:Cell Size; D002531:Cerebellum / Q000196:embryology / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D003638:Deafness / Q000235:genetics*; D005314:Embryonic and Fetal Development; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000502:physiology; D012584:Sciatic Nerve / Q000473:pathology; D012640:Seizures / Q000235:genetics*; D027981:Symporters / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters; C492280:Slc12a6 protein, mouse