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.

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

“…Our findings support observations made in Slc12a6 knockout studies revealing a gene dosage effect in Slc12a6 null compared to heterozygous knockout mice (Boettger et al, 2003;Howard et al, 2002bHoward et al, , 2003Jentsch, 2005;Rust et al, 2006).…”

“…Furthermore, several members of the cation-chloride co-transporter family are involved in hereditary diseases, such as Gitelman's, Bartter's, Gordon's and Andermann's syndromes, and have shown associations with bipolar disorder (Bianchetti et al, 1992;Dupre et al, 2003;Filteau et al, 1991;Gamba, 2005;Gitelman et al, 1966;Gordon, 1986;Howard et al, 2002bHoward et al, , 2003Meyer et al, 2005;Uyanik et al, 2006). The crucial role of cation co-transporters for neuronal development is also supported by animal studies in which knockout mice for cation-chloride co-transporters display a plethora of symptoms such as deafness, locomotor deficits, severe central and peripheral neurodegeneration, and sensorimotor gating defects (Boettger et al, 2002(Boettger et al, , 2003Hubner et al, 2001).…”

The Membrane Properties of Cochlear Root Cells are Consistent with Roles in Potassium Recirculation and Spatial Buffering

“…Siphoning is mediated by electro-neutral K/Cl co-transporters (Boettger et al 2002;Boettger et al 2003). This transport may be kept energetically favorable by a constant clearance of K + from the Deiters' cell cytoplasm, via an intercellular gap junctional pathway (Jagger and Forge 2006).…”

“…Accumulation of K + in the vicinity of hair cells is prevented by transporters expressed by underlying epithelial supporting cells (Boettger et al 2002;Boettger et al 2003;Hibino and Kurachi 2006). Supporting cells are contained within the epithelial gap junction network (Fig.…”

Insulin-like Growth Factor 1 Stimulates KCl Cotransport, Which Is Necessary for Invasion and Proliferation of Cervical Cancer and Ovarian Cancer Cells

“…The cDNA products of four KCC genes have been cloned. The activities of KCC1, KCC3, and KCC4 are osmotically sensitive and involved in cell volume regulation (3)(4)(5). The neuron-specific KCC2 is critical for the maturation of inhibitory GABA responses in the central nervous system by the control of intracellular Cl Ϫ concentration (6).…”