SLC12A5: Solute Carrier Family 12 Member 5 (KCC2)
Neuronal K-Cl Cotransporter Critical for GABAergic Inhibition and Neurodevelopmental Disorders
Gene Information Card
| Symbol | SLC12A5 |
|---|---|
| Full Name | solute carrier family 12 member 5 |
| Gene Type | protein-coding |
| Chromosomal Location | 20q13.12 |
| NCBI Gene ID | 57468 ncbi.nlm.nih.gov/gene/57468 |
| Ensembl ID | ENSG00000124140 |
| UniProt ID | Q9H2X9 |
| OMIM ID | 606726 |
| HGNC ID | 10918 |
| Aliases | KCC2, KCC-2, hKCC2, EIEE34, DEE34 |
Description
SLC12A5 encodes the neuron-specific potassium-chloride cotransporter KCC2, which extrudes Cl⁻ from neurons, establishing a low intracellular chloride concentration essential for GABAergic inhibition. KCC2 is critical for neuronal maturation, synaptic plasticity, and preventing hyperexcitability. Loss-of-function mutations lead to impaired chloride extrusion, resulting in excitatory GABA action and severe neurodevelopmental disorders including early infantile epileptic encephalopathy (EIEE34) and developmental and epileptic encephalopathy (DEE34).
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Developmental and Epileptic Encephalopathy 34 (DEE34) | Loss-of-function mutations impair KCC2 activity, elevating neuronal Cl⁻ and converting GABAergic inhibition to excitation, causing seizures and developmental delay. | ClinVar, OMIM |
| Early Infantile Epileptic Encephalopathy 34 (EIEE34) | Biallelic or dominant-negative mutations reduce KCC2 function, leading to severe neonatal-onset epilepsy and intellectual disability. | OMIM, PubMed |
| Schizophrenia (susceptibility) | Reduced KCC2 expression in prefrontal cortex disrupts GABAergic inhibition, contributing to cognitive deficits and psychosis. | NCBI Gene, PubMed |
| Autism Spectrum Disorder (ASD) | Rare SLC12A5 variants associated with altered chloride homeostasis and impaired GABAergic signaling. | ClinVar, PubMed |
| Epilepsy (generalized) | Common variants and reduced KCC2 activity linked to seizure susceptibility and pharmacoresistance. | NCBI Gene, PubMed |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 23.4 | High |
| Spinal Cord | 12.1 | Medium |
| Retina | 8.7 | Medium |
| Testis | 0.3 | Low |
| Other tissues | <0.1 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | 15.2 | Neuronal model, high KCC2 expression |
| U-87 MG (glioblastoma) | 0.8 | Low expression |
| HEK293 (embryonic kidney) | 0.1 | Negligible endogenous expression |
| iPSC-derived neurons | 22.0 | Differentiated neurons, high expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.568C>T (p.Arg190*) | Nonsense | <0.01% | Loss of function, truncated protein |
| c.679G>A (p.Gly227Arg) | Missense | <0.01% | Loss of function, impaired Cl⁻ transport |
| c.1045C>T (p.Arg349Trp) | Missense | <0.01% | Dominant-negative, reduced surface expression |
| c.1216C>T (p.Arg406Cys) | Missense | <0.01% | Loss of function, altered ion binding |
| c.1687G>A (p.Gly563Arg) | Missense | <0.01% | Loss of function, defective trafficking |
Mutation functional classification
Loss of Function (LOF)
Most SLC12A5 mutations reduce or abolish KCC2 chloride transport, leading to elevated neuronal Cl⁻ and excitatory GABA action, causing epilepsy and neurodevelopmental disorders.
Gain of Function (GOF)
No confirmed gain-of-function mutations reported in SLC12A5.
Dominant Negative (DN)
Missense mutations such as p.Arg349Trp exert dominant-negative effects by disrupting KCC2 oligomerization and surface expression, causing severe early-onset epilepsy.
View complete mutation data：
Gene Ontology (GO)
Pathways
• GABAergic synapse (KEGG: hsa04727)
• Chloride transport (Reactome: R-HSA-425393)
• Neurotransmitter receptor binding and downstream transmission (Reactome: R-HSA-112314)
• Ion transport by P-type ATPases (Reactome: R-HSA-936837)
Protein Summary
KCC2 (SLC12A5) is a 12-transmembrane domain protein that mediates electroneutral K⁺-Cl⁻ cotransport, critical for maintaining low intracellular Cl⁻ in mature neurons. It exists as two splice variants: KCC2a (full-length) and KCC2b (neuron-specific, predominant). KCC2 is essential for GABAergic inhibition; its dysfunction leads to hyperexcitability and epilepsy. The protein is regulated by phosphorylation, oligomerization, and interaction with cytoskeletal elements. KCC2 also plays roles in dendritic spine formation and neuronal migration.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SLC12A5 Knockout HEK293 Cell Line | EDJ-KQ15294 | Human | 57468 | Details Get a Quote |
| SLC12A5 Knockout A-549 Cell Line | EDJ-KQ45993 | Human | 57468 | Details Get a Quote |
| SLC12A5 Knockout HeLa Cell Line | EDJ-KQ45994 | Human | 57468 | Details Get a Quote |
| SLC12A5 Knockout HCT 116 Cell Line | EDJ-KQ73794 | Human | 57468 | Details Get a Quote |
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