On this page
SLC12A6
solute carrier family 12 member 6
The SLC12A6 gene encodes the KCC3 protein, a potassium-chloride co-transporter crucial for maintaining ion balance across cell membranes and supporting healthy nerve tissue. SLC12A6 provides instructions for making the KCC3 protein, which facilitates the movement of potassium and chlorine ions across cell membranes.
SLC12A6 is located on the long (q) arm of chromosome 15, at band 15q14. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 15 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The SLC12A6 gene, also known as KCC3, is a member of the solute carrier family 12. It plays a role in cellular ion homeostasis, specifically the co-transport of potassium and chloride ions. This function is thought to be particularly important for the normal development and ongoing health of nerve tissue throughout the body. Variants within this gene have been linked to inherited neurological conditions.
What the gene does
The SLC12A6 gene provides the blueprint for the KCC3 protein, a potassium-chloride co-transporter. This protein is situated in the cell membrane and is responsible for moving both potassium (K+) and chloride (Cl-) ions simultaneously across the membrane. This co-transport mechanism is electroneutral, meaning it does not alter the electrical charge across the membrane. While the precise molecular functions of KCC3 are still being investigated, it is believed to be critical for regulating ion concentrations, such as potassium, chloride, and water, within cells and in the spaces between cells. This regulatory role is particularly significant in the nervous system, where KCC3 appears to be essential for the proper development and maintenance of nerve cells and their axons, which are responsible for transmitting nerve impulses.
Video: Genetics 101
Chromosome location
The SLC12A6 gene is located on chromosome 15, specifically at position 15q14. This chromosomal address indicates its precise position on the long arm (q) of chromosome 15. The gene spans a region containing the genetic instructions necessary for the KCC3 protein.
Protein structure
The SLC12A6 protein, KCC3, consists of 1150 amino acids. Its structure includes a Disordered region from amino acids 20 to 66, and another Disordered region from amino acids 161 to 181. A specific Scissor helix region is found between amino acids 682 and 691. Furthermore, the protein contains an Interaction with CKB region at its C-terminus, spanning amino acids 1133 to 1150, which may be important for its functional associations.
Key variants
Genetic variations within the SLC12A6 gene can alter the structure or function of the KCC3 protein. These changes may disrupt the protein's ability to properly transport ions, which can have various effects on cellular processes. Different types of variants, including deletions and substitutions, have been identified, and their impact can range from subtle alterations in protein activity to a complete loss of function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.124C>T | p.Arg42Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.1786C>T | p.Gln596Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.1950dup | p.Leu651fs | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.2002C>T | p.Arg668Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.2180dup | p.Gly727_Asp728insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.2265G>A | p.Trp755Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.2272C>T | p.Gln758Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.2736dup | p.Val913fs | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
c.294_295del | p.Glu100fs | Pathogenic/Likely pathogenic | ★★☆☆ | SLC12A6-related disorder |
c.3061C>T | p.Arg1021Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Agenesis of the corpus callosum with peripheral neuropathy |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the SLC12A6 gene are associated with several inherited neurological conditions. These include Andermann syndrome, which is characterised by damage to nerves involved in muscle movement and sensation, and Charcot-Marie-Tooth disease, a group of inherited disorders that affect peripheral nerves. These conditions often involve impaired nerve function due to issues with the KCC3 protein's role in maintaining nerve health.
No disease links recorded for this gene in our reference set.
UK clinical status
The SLC12A6 gene is recognised within the NHS Genomic Medicine Service due to its association with inherited conditions. It is listed on several Green panels in PanelApp, indicating strong evidence for its involvement in particular disorders. These include panels for DDG2P (developmental disorders), Foetal anomalies (R21), Hereditary neuropathy, and Hereditary neuropathy or pain disorder (R78), as well as Intellectual disability.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the SLC12A6 gene do?
The SLC12A6 gene provides instructions for making the KCC3 protein, which transports potassium and chloride ions across cell membranes. This process is vital for maintaining cellular ion balance, particularly in nerve tissues.
What conditions are associated with variants in SLC12A6?
Variants in the SLC12A6 gene are linked to inherited neurological conditions such as Andermann syndrome and Charcot-Marie-Tooth disease, which affect nerve function and development.
Is SLC12A6 relevant to NHS genomic testing?
Yes, SLC12A6 is included on several Green panels within the NHS Genomic Medicine Service PanelApp, indicating its importance in the diagnosis and understanding of conditions like developmental disorders and hereditary neuropathies.
References
- Salin-Cantegrel A, Rivière JB, Dupré N. Distal truncation of KCC3 in non-French Canadian HMSN/ACC families. Neurology. 2007. PMID: 17893295
- Uyanik G, Elcioglu N, Penzien J. Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. Neurology. 2006. PMID: 16606917
- Meyer J, Johannssen K, Freitag CM. Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder. The international journal of neuropsychopharmacology. 2005. PMID: 16098236
- Hebert SC, Mount DB, Gamba G. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Pflugers Archiv : European journal of physiology. 2004. PMID: 12739168
- Dupré N, Howard HC, Mathieu J. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum. Annals of neurology. 2003. PMID: 12838516
- Howard HC, Mount DB, Rochefort D. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nature genetics. 2002. PMID: 12368912
- Race JE, Makhlouf FN, Logue PJ. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. The American journal of physiology. 1999. PMID: 10600773
- Adam MP, Bick S, Mirzaa GM. Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum. 1993. PMID: 20301546