Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold.
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.
Boettger
Thomas
T
Zentrum für Molekulare Neurobiologie, ZMNH, Universität Hamburg, Falkenried 94, D-20251 Hamburg, Germany.
Rust
Marco B
MB
Maier
Hannes
H
Seidenbecher
Thomas
T
Schweizer
Michaela
M
Keating
Damien J
DJ
Faulhaber
Jörg
J
Ehmke
Heimo
H
Pfeffer
Carsten
C
Scheel
Olaf
O
Lemcke
Beate
B
Horst
Jürgen
J
Leuwer
Rudolf
R
Pape
Hans-Christian
HC
Völkl
Harald
H
Hübner
Christian A
CA
Jentsch
Thomas J
TJ
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
D002712:Chlorides; D027981:Symporters; C119650:SLC12A6 protein, human; D000096922:K Cl- Cotransporters; C492280:Slc12a6 protein, mouse