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KCNJ1
potassium inwardly rectifying channel subfamily J member 1
The KCNJ1 gene provides instructions for making a potassium channel protein called ROMK, which is predominantly active in the kidneys and plays a key role in maintaining fluid and electrolyte balance. KCNJ1 encodes the ROMK protein, a vital potassium channel found in kidney cells.
KCNJ1 is located on the long (q) arm of chromosome 11, at band 11q24.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The KCNJ1 gene belongs to a large gene family responsible for producing potassium channels, which are integral to the movement of positively charged potassium ions into and out of cells. These channels are critical for generating and transmitting electrical signals within cells. The ROMK protein, encoded by KCNJ1, is predominantly expressed in the kidneys, where it contributes significantly to the regulation of ion transport and fluid balance.
What the gene does
The KCNJ1 gene produces a protein known as ROMK, which functions as a potassium channel. In the kidneys, ROMK channels are involved in the intricate process of ion movement across cell membranes. Specifically, the transport of potassium ions facilitated by ROMK is necessary for the proper function of another ion transporter, NKCC2, which is involved in the reabsorption of sodium chloride (salt) from urine back into the bloodstream. This reabsorption of salt is vital for regulating the body's fluid levels and maintaining healthy blood pressure. Changes in ROMK function can therefore disrupt electrolyte balance and fluid homeostasis.
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Chromosome location
The KCNJ1 gene is located on chromosome 11, specifically at band 11q24.3. This chromosomal region contains the genetic instructions for the ROMK protein, which is 391 amino acids in length.
Protein structure
The ROMK protein, encoded by the KCNJ1 gene, contains several important functional regions. A critical component is the Selectivity filter, spanning amino acids 141-146, which is crucial for distinguishing potassium ions from other ions. Additionally, the protein includes a Polyphosphoinositide (PIP2)-binding region from amino acids 180-207, which is important for regulating channel activity.
Key variants
Variants in the KCNJ1 gene can alter the structure and function of the ROMK potassium channel. These genetic changes can range from single amino acid substitutions to larger deletions or insertions within the gene. Such variants may impair the channel's ability to transport potassium ions effectively, leading to downstream effects on kidney function and electrolyte balance.
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.251C>T | p.Ala84Val | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
c.272C>T | p.Pro91Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
c.416_417del | p.Phe139fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
c.504dup | p.Arg169fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
c.874C>T | p.Arg292Trp | Pathogenic | ★★☆☆ | Bartter syndrome |
c.875G>A | p.Arg292Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
c.887T>G | p.Val296Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.89G>A | p.Cys30Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter syndrome |
c.939_942del | p.Glu315fs | Pathogenic | ★★☆☆ | Bartter disease type 2 |
c.983del | p.Thr328fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 2 |
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
Pathogenic variants in the KCNJ1 gene are primarily associated with Bartter syndrome, an inherited condition affecting kidney function. Specifically, mutations in KCNJ1 are known to cause Bartter syndrome type II, a severe form of the disorder that often presents with significant health problems at or shortly after birth. These genetic changes interfere with the kidney's ability to reabsorb salt and water, leading to electrolyte imbalances.
Inheritance pattern
Conditions caused by pathogenic KCNJ1 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
The KCNJ1 gene is included in several NHS Genomic Medicine Service national test panels. It is listed as 'green' for Foetal anomalies (R21), Nephrocalcinosis or nephrolithiasis (R256), and Renal tubulopathies (R198), indicating that there is strong evidence for its association with these conditions and it is routinely tested in relevant clinical contexts within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the KCNJ1 gene?
The KCNJ1 gene provides instructions for making a protein called ROMK, which acts as a potassium channel. This channel is mainly found in the kidneys and helps regulate the movement of potassium ions, which is crucial for maintaining the body's fluid and electrolyte balance.
What health conditions are associated with KCNJ1 variants?
Pathogenic variants in the KCNJ1 gene are primarily associated with Bartter syndrome, particularly type II. This condition affects kidney function, leading to electrolyte imbalances and fluid regulation issues, often presenting with severe symptoms early in life.
How does KCNJ1 affect kidney function?
KCNJ1 produces the ROMK protein, a potassium channel essential for kidney cells to properly reabsorb salt (sodium chloride) from urine back into the bloodstream. This process is vital for regulating the body's fluid levels and maintaining normal blood pressure.
References
- Welling PA, Ho K. A comprehensive guide to the ROMK potassium channel: form and function in health and disease. American journal of physiology. Renal physiology. 2009. PMID: 19458126
- Ji W, Foo JN, O'Roak BJ. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nature genetics. 2008. PMID: 18391953
- Tobin MD, Tomaszewski M, Braund PS. Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population. Hypertension (Dallas, Tex. : 1979). 2008. PMID: 18443236
- Peters M, Ermert S, Jeck N. Classification and rescue of ROMK mutations underlying hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney international. 2003. PMID: 12911542
- Jeck N, Derst C, Wischmeyer E. Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney international. 2001. PMID: 11318951
- Derst C, Konrad M, Köckerling A. Mutations in the ROMK gene in antenatal Bartter syndrome are associated with impaired K+ channel function. Biochemical and biophysical research communications. 1997. PMID: 9015377
- Simon DB, Karet FE, Rodriguez-Soriano J. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nature genetics. 1996. PMID: 8841184