Chloride channel protein ClC-Ka is aprotein that in humans is encoded by theCLCNKAgene. Multiple transcript variants encoding different isoforms have been found for this gene.[5][6]
This gene is a member of the CLC family of voltage-gatedchloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit calledbarttin to form a functional channel. It is thought to function in salt reabsorption in the kidney and potassium recycling in the inner ear. The gene is highly similar toCLCNKB, which is located 10 kb downstream from this gene.[6]
CLCNKA encodes one of the two major chloride channels found in the kidney, the ClC-Ka channel (the other class being the ClC-Kb from CLCNKB). The CLCNKA gene is subject, like all genes, to variation due tosingle-nucleotide polymorphisms (SNPs), in which a single base (A, T, C, or G) is randomly replaced by another base.[7] SNPs in the coding regions of CLCKNA may have consequent changes in the amino acid sequence of the ClC-Ka chloride channel leading to altered functional capacities and subsequent physiological alterations.[7]
Four SNPs (rs848307, rs1739843, rs1010069, and rs1805152) have been associated with increased salt-sensitivity by displaying an irregularly large increase in blood pressure following modest salt (Na+) intake, despite regular heart rate, blood pressure, and plasma renin levels before the salt ingestion.[7] Of particular interest is a common SNP leading to the amino acid Arginine at the 83rd position to be replaced by Glycine.[8] This variant is found to exist in approximately half of all caucasians, while a quarter of caucasians are homozygous for the allele.[8] Although mainly studied in the context of caucasians, the SNP actually exists with a greater frequency in people of African descent, where the gene frequency is 70%.[8] This SNP (rs10927887) was originally implicated in congestive heart failure after investigations into the heat shock protein HSPB7 showed that the CLCNKA gene was inlinkage disequilibrium, meaning that the two genes are often not separated during recombination.[8] The CLCNKA variant was then shown to be the cause of the pathology.[8]
The four SNPs found to be associated with salt sensitivity consequently predispose such cardiovascular problems asleft ventricular hypertrophy and dysfunction of the endothelium.[7] The Arg83Gly SNP specifically results in a large reduction in the flow of chloride ions through the ClC-Ka channel in the thin and thick ascending limb of the nephrons.[8] Experimentally, the membrane potential at which the channels show no net movement of ions at a given chloride concentration drops significantly with the mutation, indicating altered function in situ.[8] This manifests as a chronic salt wasting disorder similar toBartter syndrome,[8] as sodium reabsorption is coupled with chloride reabsorption.[7] The salt loss results in a decreased blood volume and consequently hyperreninemia leading (via the end product angiotensin II and aldosterone) to increased vascular tone, heart rate, water reabsorption, and blood pressure, collectively referred to ascardiorenal syndrome.[8] Being heterozygous for this Arg83Gly variant increases the risk of heart failure by 27%, while homozygosity increases the risk by 54%.[8] The additive stress on the heart from increased blood pressure and heart rate often only manifests as a pathology with an additional cardiovascular problem such as hypertension.[8] Treatment for the SNP associated hyperreninemia involves drugs to block the Renin-Angiotensin-Aldosterone system to relieve the aforementioned stresses on the heart.[8]
Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides".Gene.138 (1–2):171–4.doi:10.1016/0378-1119(94)90802-8.PMID8125298.
Saito-Ohara F, Uchida S, Takeuchi Y, Sasaki S, Hayashi A, Marumo F, Ikeuchi T (1997). "Assignment of the genes encoding the human chloride channels, CLCNKA and CLCNKB, to 1p36 and of CLCN3 to 4q32-q33 by in situ hybridization".Genomics.36 (2):372–4.doi:10.1006/geno.1996.0479.PMID8812470.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library".Gene.200 (1–2):149–56.doi:10.1016/S0378-1119(97)00411-3.PMID9373149.
Estévez R, Boettger T, Stein V, Birkenhäger R, Otto E, Hildebrandt F, Jentsch TJ (2002). "Barttin is a Cl− channel beta-subunit crucial for renal Cl− reabsorption and inner ear K+ secretion".Nature.414 (6863):558–61.doi:10.1038/35107099.PMID11734858.S2CID4407807.
