CLCNKA | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | CLCNKA , CLCK1, ClC-K1, hClC-Ka, chloride voltage-gated channel Ka | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 602024 MGI: 1930643 HomoloGene: 107317 GeneCards: CLCNKA | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Chloride channel protein ClC-Ka is a protein that in humans is encoded by the CLCNKA gene. 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-gated chloride channels. The encoded protein is predicted to have 12 transmembrane domains, and requires a beta subunit called barttin 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 to CLCNKB, 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 to single-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 in linkage 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 as left 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 to Bartter 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 as cardiorenal 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]
Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration in vivo is much higher than other anions. Several families of voltage-gated channels and ligand-gated channels have been characterized in humans.
Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.
The renal outer medullary potassium channel (ROMK) is an ATP-dependent potassium channel (Kir1.1) that transports potassium out of cells. It plays an important role in potassium recycling in the thick ascending limb (TAL) and potassium secretion in the cortical collecting duct (CCD) of the nephron. In humans, ROMK is encoded by the KCNJ1 gene. Multiple transcript variants encoding different isoforms have been found for this gene.
Fibroblast growth factor 23 (FGF23) is a protein and member of the fibroblast growth factor (FGF) family which participates in the regulation of phosphate in plasma and vitamin D metabolism. In humans it is encoded by the FGF23 gene. FGF23 decreases reabsorption of phosphate in the kidney. Mutations in FGF23 can lead to its increased activity, resulting in autosomal dominant hypophosphatemic rickets.
The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.
Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.
Transient receptor potential cation channel subfamily V member 5 is a calcium channel protein that in humans is encoded by the TRPV5 gene.
The CLCN family of voltage-dependent chloride channel genes comprises nine members which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen).
The CLCN5 gene encodes the chloride channel Cl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of albumin and low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells. Mutations in the CLCN5 gene cause an X-linked recessive nephropathy named Dent disease characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis and nephrolithiasis.
Chloride channel protein 2 is a protein that in humans is encoded by the CLCN2 gene. Mutations of this gene have been found to cause leukoencephalopathy and Idiopathic generalised epilepsy, although the latter claim has been disputed. CLCN2 contains a transmembrane region that is involved in chloride ion transport as well two intracellular copies of the CBS domain.
Chloride channel Kb, also known as CLCNKB, is a protein which in humans is encoded by the CLCNKB gene.
Anion exchange protein 3 is a membrane transport protein that in humans is encoded by the SLC4A3 gene. AE3 is functionally similar to the Band 3 Cl−/HCO3− exchange protein but it is expressed primarily in brain neurons and in the heart. Like AE2 its activity is sensitive to pH. AE3 mutations have been linked to seizures.
Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.
Chloride intracellular channel protein 2 is a protein that in humans is encoded by the CLIC2 gene.
Chloride transport protein 6 is a protein that in humans is encoded by the CLCN6 gene.
Solute carrier family 22, member 12, also known as SLC22A12 and URAT1, is a protein which in humans is encoded by the SLC22A12 gene.
The Cl−-formate exchanger, otherwise known as Pendrin encoded by the SLC26A4 gene, is a transport protein present in the kidney, where it functions in the renal chloride reabsorption. It is also present in vascular smooth muscle and cardiac muscle.
Bartter syndrome, infantile, with sensorineural deafness (Barttin), also known as BSND, is a human gene which is associated with Bartter syndrome.
Solute carrier family 12 member 6 is a protein that in humans is encoded by the SLC12A6 gene.
Chloride intracellular channel protein 5 is a protein that in humans is encoded by the CLIC5 gene.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.