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KCNJ10
potassium inwardly rectifying channel subfamily J member 10
KCNJ10 is located on the long (q) arm of chromosome 1, at band 1q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
KCNJ10 (potassium inwardly rectifying channel subfamily J member 10) is located on chromosome 1q23.2 and encodes a specialised ion channel protein comprising 379 amino acids. The protein functions as part of an inward-rectifier potassium channel, a family of membrane proteins that preferentially allow potassium ions to flow into cells rather than out. These channels are particularly important in tissues that require precise control of the electrical and chemical environment surrounding cells, including the renal tubules, the inner ear structures responsible for hearing, and glial cells in the central nervous system. Pathogenic variants in KCNJ10 follow an autosomal recessive inheritance pattern, meaning that an individual must inherit altered copies from both parents to develop associated conditions.
What the gene does
The KCNJ10 protein assembles with other subunits to form functional potassium channels in the cell membrane. These channels regulate the flow of potassium ions based on the electrical potential across the membrane, helping to maintain stable potassium concentrations in the fluid surrounding cells. In the kidney, KCNJ10 channels expressed in the distal convoluted tubule support reabsorption of sodium and magnesium whilst facilitating potassium secretion, thereby contributing to overall electrolyte homeostasis and blood pressure regulation. Within the inner ear, the channel helps maintain the unique ionic composition of the endolymph, the fluid that bathes sensory hair cells and is essential for converting sound vibrations into electrical signals. In the brain, KCNJ10 is predominantly expressed in astrocytes and other glial cells, where it participates in buffering extracellular potassium released during neuronal activity. By clearing excess potassium from the space around neurons, these channels help prevent abnormal excitability that could lead to seizures or other neurological disturbances.
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Chromosome location
KCNJ10 is located on the long arm of chromosome 1 at position 23.2 (1q23.2). The gene spans a modest genomic region and encodes a relatively compact protein. Detailed exon structure varies across transcript isoforms, but the primary coding sequence encodes the 379-amino-acid channel protein that integrates into cellular membranes.
Protein structure
The KCNJ10 protein belongs to the inward-rectifier potassium channel family and contains the characteristic architecture of this protein class. Each subunit features two transmembrane segments that span the lipid bilayer, connected by a pore-forming loop. The selectivity filter, a conserved motif spanning amino acids 128 to 133, determines the channel's preference for potassium ions over other cations by providing a narrow passage lined with oxygen atoms that stabilise dehydrated potassium. Four KCNJ10 subunits assemble to create a functional channel, with the selectivity filters from each subunit converging to form the ion-conducting pathway. The cytoplasmic portions of the protein contain regulatory regions that modulate channel activity in response to intracellular signals.
Key variants
Pathogenic variants in KCNJ10 disrupt the normal function of the potassium channel, most commonly through missense changes that alter critical residues within the pore region or transmembrane domains. These alterations can reduce the channel's ability to conduct potassium ions, impair its assembly into functional complexes, or destabilise the protein. Because KCNJ10-related conditions follow autosomal recessive inheritance, affected individuals typically carry two pathogenic variants, one inherited from each parent.
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.500C>T | p.Ala167Val | Pathogenic | ★★☆☆ | EAST syndrome |
c.595C>T | p.Arg199Ter | Pathogenic/Likely pathogenic | ★★☆☆ | EAST syndrome |
c.889C>T | p.Arg297Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 4 |
c.19_20insC | p.Val7fs | Pathogenic | ★☆☆☆ | EAST syndrome |
c.198C>G | p.Tyr66Ter | Pathogenic | ★☆☆☆ | EAST syndrome |
c.211_212del | p.Phe71fs | Pathogenic | ★☆☆☆ | EAST syndrome |
c.236G>A | p.Trp79Ter | Pathogenic | ★☆☆☆ | EAST syndrome |
c.331C>T | p.Gln111Ter | Pathogenic | ★☆☆☆ | EAST syndrome |
c.68del | p.Pro23fs | Pathogenic | ★☆☆☆ | EAST syndrome |
c.798dup | p.Asp267fs | Pathogenic | ★☆☆☆ | EAST syndrome |
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
Biallelic pathogenic variants in KCNJ10 cause EAST syndrome, also known as SeSAME syndrome. The acronym EAST stands for Epilepsy, Ataxia, Sensorineural deafness, and Tubulopathy, reflecting the four cardinal features of this multisystem disorder. Individuals with EAST syndrome typically present in infancy or early childhood with seizures, developmental delays, and progressive hearing loss. The renal tubulopathy manifests as salt wasting, leading to low levels of potassium and magnesium in the blood. Affected individuals often exhibit unsteady movement (ataxia) due to involvement of the cerebellum and may have intellectual disability of variable severity.
Inheritance pattern
Conditions caused by pathogenic KCNJ10 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
KCNJ10 is included on multiple NHS Genomic Medicine Service gene panels, reflecting its relevance to several clinical presentations. The gene holds green (high evidence) status on the Renal tubulopathies panel (R198), the Early onset or syndromic epilepsy panel (R59), the Intellectual disability panel (R29), and the Monogenic hearing loss panel (R67). It is also listed on the Hereditary ataxia panel (R54), the Ataxia and cerebellar anomalies narrow panel, and DDG2P. This multi-panel inclusion underscores the diverse clinical manifestations associated with KCNJ10 variants and supports genetic testing for individuals presenting with combinations of seizures, hearing loss, ataxia, renal electrolyte abnormalities, or developmental concerns.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does inward-rectifier mean for a potassium channel?
Inward-rectifier potassium channels preferentially allow potassium ions to flow into cells rather than out, helping to stabilise the electrical potential across the cell membrane. This directional preference is important for maintaining proper cellular excitability and ion balance in tissues such as the kidney and brain.
How is EAST syndrome diagnosed?
Diagnosis typically involves clinical recognition of the characteristic combination of seizures, ataxia, sensorineural hearing loss, and renal salt wasting, supported by laboratory findings of low blood potassium and magnesium. Genetic testing confirming biallelic pathogenic variants in KCNJ10 provides definitive molecular diagnosis.
Can carriers of one KCNJ10 variant develop symptoms?
Carriers who inherit a single pathogenic KCNJ10 variant typically do not develop EAST syndrome, as the condition follows autosomal recessive inheritance. Two altered copies, one from each parent, are generally required for clinical manifestations to occur.