Gene Symbol: Slc12a6
Description: solute carrier family 12, member 6
Alias: 9530023I19Rik, KCC3, gaxp, solute carrier family 12 member 6, K-Cl cotransporter 3, electroneutral potassium-chloride cotransporter 3
Species: mouse
Products:     Slc12a6

Top Publications

  1. Boettger T, Rust M, Maier H, Seidenbecher T, Schweizer M, Keating D, et al. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 2003;22:5422-34 pubmed
    ..b>KCC3, an isoform mutated in the human Anderman syndrome, is expressed in brain, epithelia and other tissues...
  2. Howard H, Mount D, Rochefort D, Byun N, Dupre N, Lu J, et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002;32:384-92 pubmed
    ..ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN ..
  3. Rust M, Faulhaber J, Budack M, Pfeffer C, Maritzen T, Didié M, et al. Neurogenic mechanisms contribute to hypertension in mice with disruption of the K-Cl cotransporter KCC3. Circ Res. 2006;98:549-56 pubmed
    ..Mice with a targeted disruption of the corresponding gene, Slc12a6, reproduce neurodegeneration of the peripheral and central nervous system (CNS) and display arterial hypertension...
  4. Byun N, Delpire E. Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice. Neurobiol Dis. 2007;28:39-51 pubmed
    We have previously reported CNS and locomotor deficits in KCC3 knockout mice, an animal model of agenesis of the corpus callosum associated with peripheral neuropathy (ACCPN) [Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupre, N...
  5. Shekarabi M, Salin Cantegrel A, Laganiere J, Gaudet R, Dion P, Rouleau G. Cellular expression of the K+-Cl- cotransporter KCC3 in the central nervous system of mouse. Brain Res. 2011;1374:15-26 pubmed publisher
    ..Potassium/Chloride cotransporter 3 (KCC3) mutations are responsible for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/..
  6. Shekarabi M, Moldrich R, Rasheed S, Salin Cantegrel A, Laganiere J, Rochefort D, et al. Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. J Neurosci. 2012;32:3865-76 pubmed publisher
    Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and ..
  7. Blaesse P, Airaksinen M, Rivera C, Kaila K. Cation-chloride cotransporters and neuronal function. Neuron. 2009;61:820-38 pubmed publisher
    ..The rapidly expanding work on CCCs promotes our understanding of fundamental mechanisms that control brain development and functions under normal and pathophysiological conditions. ..
  8. Adragna N, Chen Y, Delpire E, Lauf P, Morris M. Hypertension in K-Cl cotransporter-3 knockout mice. Adv Exp Med Biol. 2004;559:379-85 pubmed
  9. Seja P, Schonewille M, Spitzmaul G, Badura A, Klein I, Rudhard Y, et al. Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning. EMBO J. 2012;31:1217-30 pubmed publisher
    ..In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl(-)](i) roughly two-fold...

More Information


  1. Rust M, Alper S, Rudhard Y, Shmukler B, Vicente R, Brugnara C, et al. Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest. 2007;117:1708-17 pubmed
    ..To address the roles of individual K-Cl cotransporter isoforms in rbc volume homeostasis, we disrupted the Kcc1 and Kcc3 genes in mice...
  2. Kahle K, Flores B, Bharucha Goebel D, Zhang J, Donkervoort S, Hegde M, et al. Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. Sci Signal. 2016;9:ra77 pubmed publisher
    Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily ..
  3. Mercado A, Vazquez N, Song L, Cortés R, Enck A, Welch R, et al. NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter. Am J Physiol Renal Physiol. 2005;289:F1246-61 pubmed
    The SLC12A6 gene encoding the K(+)-Cl(-) cotransporter KCC3 is expressed in multiple tissues, including kidney...
  4. Ding J, Ponce Coria J, Delpire E. A trafficking-deficient mutant of KCC3 reveals dominant-negative effects on K-Cl cotransport function. PLoS ONE. 2013;8:e61112 pubmed publisher
    ..In the process of cloning the mouse KCC3 cDNA, we came across a cloning mutation (E289G) that rendered the cotransporter inactive in functional assays in ..
  5. Melo Z, Cruz Rangel S, Bautista R, Vazquez N, Castañeda Bueno M, Mount D, et al. Molecular evidence for a role for K(+)-Cl(-) cotransporters in the kidney. Am J Physiol Renal Physiol. 2013;305:F1402-11 pubmed publisher
    K(+)-Cl(-) cotransporter (KCC) isoforms 3 (KCC3) and 4 (KCC4) are expressed at the basolateral membrane of proximal convoluted tubule cells, and KCC4 is present in the basolateral membrane of the thick ascending loop of Henle's limb and ?-..
  6. Trowe M, Maier H, Petry M, Schweizer M, Schuster Gossler K, Kispert A. Impaired stria vascularis integrity upon loss of E-cadherin in basal cells. Dev Biol. 2011;359:95-107 pubmed publisher
  7. Sun Y, Shieh C, Delpire E, Shen M. K?-Cl? cotransport mediates the bactericidal activity of neutrophils by regulating NADPH oxidase activation. J Physiol. 2012;590:3231-43 pubmed publisher
    ..Inhibition of KCC activity or knockdown of KCC expression, in particular KCC3, reduced the phosphorylation as well as the membrane recruitment of oxidase components...
  8. Lucas O, Hilaire C, Delpire E, Scamps F. KCC3-dependent chloride extrusion in adult sensory neurons. Mol Cell Neurosci. 2012;50:211-20 pubmed publisher
    ..In post-natal sensory neurons, quantitative RT-PCR showed that NKCC1, KCC1 and KCC3 had a higher transcript expression level compared to KCC2 and KCC4...
  9. Piechotta K, Lu J, Delpire E. Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem. 2002;277:50812-9 pubmed
    ..Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1) with the cotransporters KCC3, NKCC1, and NKCC2 but not KCC1 and KCC4...
  10. Ding J, Delpire E. Deletion of KCC3 in parvalbumin neurons leads to locomotor deficit in a conditional mouse model of peripheral neuropathy associated with agenesis of the corpus callosum. Behav Brain Res. 2014;274:128-36 pubmed publisher
    ..of the corpus callosum (HMSN/ACC or ACCPN) is an autosomal recessive disease caused by the disruption of the SLC12A6 gene, which encodes the K-Cl cotransporter-3 (KCC3)...
  11. Garneau A, Marcoux A, Noël M, Frenette Cotton R, Drolet M, Couet J, et al. Ablation of Potassium-Chloride Cotransporter Type 3 (Kcc3) in Mouse Causes Multiple Cardiovascular Defects and Isosmotic Polyuria. PLoS ONE. 2016;11:e0154398 pubmed publisher
    Inactivation of Kcc3 in a mixed 129/Sv×C57BL/6 mouse background has been previously found to increase systemic blood pressure (BP) through presumed neurogenic mechanisms...
  12. Li Z, Mulligan M, Wang X, Miles M, Lu L, Williams R. A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice. PLoS ONE. 2010;5:e12181 pubmed publisher
    ..The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains. ..
  13. Sun Y, Lin T, Tzeng S, Delpire E, Shen M. Deficiency of electroneutral K+-Cl- cotransporter 3 causes a disruption in impulse propagation along peripheral nerves. Glia. 2010;58:1544-52 pubmed publisher
    ..Mutation in SLC12A6 gene encoding KCC3 results in an autosomal recessive disease, known as agenesis of the corpus callosum associated ..
  14. Mount D, Mercado A, Song L, Xu J, George A, Delpire E, et al. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J Biol Chem. 1999;274:16355-62 pubmed
    ..We have cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members of this gene family...
  15. Pan D, Kalfa T, Wang D, Risinger M, Crable S, Ottlinger A, et al. K-Cl cotransporter gene expression during human and murine erythroid differentiation. J Biol Chem. 2011;286:30492-503 pubmed publisher
    ..Western blot analysis of RBC membranes revealed KCC1, KCC3, and KCC4 proteins in mouse and human cells, with higher levels in reticulocytes...
  16. Salin Cantegrel A, Shekarabi M, Holbert S, Dion P, Rochefort D, Laganiere J, et al. HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3. Hum Mol Genet. 2008;17:2703-11 pubmed publisher
    The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in ..
  17. Trowe M, Maier H, Schweizer M, Kispert A. Deafness in mice lacking the T-box transcription factor Tbx18 in otic fibrocytes. Development. 2008;135:1725-34 pubmed publisher
  18. Jiao Y, Jin X, Yan J, Zhang C, Jiao F, Li X, et al. A deletion mutation in Slc12a6 is associated with neuromuscular disease in gaxp mice. Genomics. 2008;91:407-14 pubmed publisher
    ..Based on microarray data and the known function of genes identified, Slc12a6 was selected as the primary candidate gene and analyzed using the Reveal technology of SpectruMedix...
  19. Sun Y, Tzeng S, Lin T, Hsu K, Delpire E, Shen M. KCC3 deficiency-induced disruption of paranodal loops and impairment of axonal excitability in the peripheral nervous system. Neuroscience. 2016;335:91-102 pubmed publisher
    ..of the Corpus Callosum (HMSN/ACC) is associated with the dysfunction of the K(+)-Cl(-) cotransporter type 3 (KCC3), which is an electroneutral cotransporter...
  20. Hübner C, Stein V, Hermans Borgmeyer I, Meyer T, Ballanyi K, Jentsch T. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515-24 pubmed
    ..Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition. ..
  21. Pearson M, Lu J, Mount D, Delpire E. Localization of the K(+)-Cl(-) cotransporter, KCC3, in the central and peripheral nervous systems: expression in the choroid plexus, large neurons and white matter tracts. Neuroscience. 2001;103:481-91 pubmed
    ..Several K(+)-Cl(-) cotransporter isoforms are expressed in the nervous system, and KCC3 in particular is expressed at significant levels in both the brain and spinal cord...