CLCN5

Last updated
CLCN5
Protein CLCN5 PDB 2j9l.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CLCN5 , CLC5, CLCK2, ClC-5, DENTS, NPHL1, NPHL2, XLRH, XRN, hCIC-K2, chloride voltage-gated channel 5, DENT1
External IDs OMIM: 300008; MGI: 99486; HomoloGene: 73872; GeneCards: CLCN5; OMA:CLCN5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000084
NM_001127898
NM_001127899
NM_001272102
NM_001282163

Contents

NM_001243762
NM_016691

RefSeq (protein)

NP_000075
NP_001121370
NP_001121371
NP_001259031
NP_001269092

NP_001230691
NP_057900

Location (UCSC) Chr X: 49.92 – 50.1 Mb Chr X: 7.02 – 7.19 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 (Dent disease 1 MIM#300009) characterized by excessive urinary loss of low-molecular-weight proteins and of calcium (hypercalciuria), nephrocalcinosis (presence of calcium phosphate aggregates in the tubular lumen and/or interstitium) and nephrolithiasis (kidney stones).

The CLCN5 gene

Structure

The human CLCN5 gene (MIM#300008, reference sequence NG_007159.2) is localized in the pericentromeric region on chromosome Xp11.23. It extends over about 170 Kb of genomic DNA, has a coding region of 2,238 bp and consists of 17 exons including 11 coding exons (from 2 to 12). [5] [6] [7] [8] The CLCN5 gene has 8 paralogues ( CLCN1 , CLCN2 , CLCN3 , CLCN4, CLCN6 , CLCN7 , CLCNKA , CLCNKB ) and 201 orthologues among jawed vertebrates ( Gnathostomata ).

Five different CLCN5 gene transcripts have been discovered, two of which (transcript variants 3 [NM_000084.5] and 4 [NM_001282163.1]) encode for the canonical 746 amino acid protein, two (transcript variants 1 [NM_001127899.3] and 2 [NM_001127898.3]) for the NH2-terminal extended 816 amino acid protein [9] and one does not encode for any protein (Transcript variant 5, [NM_001272102.2]). The 5’ untranslated region (5’UTR) of CLCN5 is complex and not entirely clarified. Two strong and one weak promoters were predicted to be present in the CLCN5 gene. [10] [11] Several different 5’ alternatively used exons have been recognized in the human kidney. [9] [10] [11] [12] The three promoters drive with varying degree of efficiency 11 different mRNAs, with transcription initiating from at least three different start sites. [10]

The chloride channel H+/Cl exchanger ClC-5

Like all ClC channels, ClC-5 needs to dimerize to create the pore through which the ions pass. [13] [14] [15] ClC-5 can form both homo- and hetero-dimers due to its marked sequence homology with ClC-3 and ClC-4. [16] [17] [18]

The canonical 746-amino acid ClC-5 protein has 18 membrane spanning α-helices (named A to R), an intracellular N- terminal domain and a cytoplasmic C-terminus containing two cystathionine beta-synthase (CBS) domains which are known to be involved in the regulation of ClC-5 activity. [13] [19] [20] [21] Helices B, H, I, O, P, and Q are the six major helices involved in the formation of dimer’s interface and are crucial for proper pore configuration. [13] [14] The Cl selectivity filter is principally driven by helices D, F, N, and R, which are conveyed together near the channel center. [13] [14] [22] [23] Two important amino acids for the proper ClC-5 function are the glutamic acids at position 211 and 268 called respectively “gating glutamate” and “proton glutamate”. [24] [25] [26] [27] The gating glutamate is necessary for both H+ transport and ClC-5 voltage dependence. [8] [28] [29] The proton glutamate is crucial to the H+ transport acting as an H+ transfer site. [24] [30] [31]

Localization and function

ClC-5 belongs to the family of voltage gated chloride channel that are regulators of membrane excitability, transepithelial transport and cell volume in different tissues. Based on sequence homology, the nine mammalian ClC proteins can be grouped into three classes, of which the first (ClC-1, ClC-2, ClC-Ka and ClC-Kb) is expressed primarily in plasma membranes, whereas the other two (ClC-3, ClC-4, and ClC-5 and ClC-6 and ClC-7) are expressed primarily in organellar membranes. [32]

ClC-5 is expressed in minor to moderate level in brain, muscle, intestine but highly in the kidney, primarily in proximal tubular cells of S3 segment, in alfa intercalated cells of cortical collecting duct of and in cortical and medullary thick ascending limb of Henle’s loop. [33] [34] [35] [36] [37] [38]

Proximal tubular cells (PTCs) are the main site of ClC-5 expression. By means of the receptor-mediated endocytosis process, they uptake albumin and low-molecular-weight proteins freely passed through the glomerular filter. ClC-5 is located in early endosomes of PTCs where it co-localizes with the electrogenic vacuolar H+‐ATPase (V‐ATPase). [34] [38] ClC-5 in this compartment contributes to the maintenance of intra-endosomal acidic pH. Environment acidification is necessary for the dissociation of ligand from its receptor. The receptor is then recycled to the apical membrane, while ligand is transported to the late endosome and lysosome where it is degraded. ClC-5 supports efficient acidification of endosomes either by providing a Cl conductance to counterbalance the accumulation of positively charged H+ pumped in by V-ATPase or by directly acidifying endosome in parallel with V-ATPase. [39]

Experimental evidence indicates that endosomal Cl concentration, which is raised by ClC-5 in exchange for protons accumulated by the V-ATPase, may play a role in endocytosis independently from endosomal acidification, thus pointing to another possible mechanism by which ClC-5 dysfunction may impair endocytosis. [40]

ClC-5 is located also at the cell surface of PTCs where probably it plays a role in the formation/function of the endocytic complex that also involves megalin and cubilin/amnionless receptors, the sodium-hydrogen antiporter 3 (NHE3), and the V-ATPase. [41] [42] It was demonstrated at the C-terminus of ClC-5 binds the actin-depolymerizing protein cofilin. When the nascent endosome forms, the recruitment of cofilin by ClC-5 is a prerequisite for the localized dissolution of the actin cytoskeleton, thus permitting the endosome to pass into the cytoplasm. It is conceivable that at the cell surface, the large intracellular C-terminus of ClC-5 has a crucial function in mediating the assembly, stabilization and disassembly of the endocytic complex via protein–protein interactions. Therefore, ClC-5 may accomplish two roles in the receptor-mediated endocytosis: i) vesicular acidification and receptor recycling; ii) participation to the non-selective megalin–cubilin-amnionless low-molecular-weight protein uptake at the apical membrane. [41]

Clinical significance

Dent disease is mainly caused by loss-of-function mutations in the CLCN5 gene (Dent disease 1; MIM#300009). [14] [43] Dent disease 1 shows a marked allelic heterogeneity. To date, 265 different CLCN5 pathogenic variants have been described. [14] A small number of pathogenic variants were found in more than one family. [44] The 48% are truncating mutations (nonsense, frameshift or complex), 37% non-truncating (missense or in-frame insertions/deletions), 10% splice site mutations, and 5% other type (large deletions, Alu insertions or 5’UTR mutations). Functional investigations in Xenopus laevis oocytes and mammalian cells [39] [43] [45] [46] [47] [40] enabled these CLCN5 mutations to be classified according to their functional consequences. [8] [44] [48] [49] [50] The most common mutations lead to a defective protein folding and processing, resulting in endoplasmic reticulum retention of the mutant protein for further degradation by the proteasome.

Animal models

Two independent ClC-5 knock-out mice, the so called Jentsch [51] [52] and Guggino models, [53] [54] [55] [56] provided critical insights into the mechanisms of proximal tubular dysfunction in Dent disease 1. These two murine models recapitulated the major features of Dent disease (low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis) and demonstrated that ClC-5 inactivation is associated with severe impairment of both fluid phase and receptor-mediated endocytosis, as well as trafficking defects leading to the loss of megalin and cubilin at the brush border of proximal tubules. However, targeted disruption of ClC-5 in the Jentsch model did not lead to hypercalciuria, kidney stones or nephrocalcinosis, while the Guggino model did. [53] The Jentsch murine model produced slightly more acidic urines. Urinary phosphate excretion was increased in both models by about 50%. Hyperphosphaturia in the Jentsch model was associated with decreased apical expression of the sodium/phosphate cotransporter NaPi2a that is the predominant phosphate transporter in the proximal tubule. However, NaPi2a expression is ClC-5-independent since apical NaPi2a was normally expressed in any proximal tubules of chimeric female mice, while it was decreased in all male proximal tubular knock-out cells. Serum parathormone (PTH) is normal in knock-out mice while urinary PTH is increased of about 1.7 fold.  Megalin usually mediates the endocytosis and degradation of PTH in proximal tubular cells. In knock-out mice, the downregulation of megalin leads to PTH defective endocytosis and progressively increases luminal PTH levels that enhance the internalization of NaPi2a. [51]

DNA testing and genetic counselling

A clinical diagnosis of Dent disease can be confirmed through molecular genetic testing that can detect mutations in specific genes known to cause Dent disease. However, about 20-25% of Dent disease patients remain genetically unresolved. [44]

Genetic testing is useful to determine the status of healthy carrier in the mother of an affected male. In fact, being Dent disease an X-linked recessive disorder, males are more frequently affected than females, and females may be heterozygous healthy carrier. Due to skewed X-inactivation, female carriers may present some mild symptoms of Dent disease such as low-molecular-weight proteinuria or hypercalciuria. Carriers will transmit the disease to half of their sons whereas half of their daughters will be carriers. Affected males do not transmit the disease to their sons since they pass Y chromosome to males, but all their daughters will inherited mutated X chromosome. Preimplant and prenatal genetic testing is not advised for Dent disease 1 since the prognosis for the majority of the patients is good and a clear correlation between genotype and phenotype is lacking. [57]

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

An antiporter is an integral membrane protein involved in secondary active transport. It is a type of cotransporter, which means that uses the movement of one In the case of an antiporter, two or more different molecules or ions are moved across a phospholipid membrane, such as the plasma membrane, in opposite directions, one into the cell and one out of the cell. This is in contrast to symporters, which are another type of cotransporter that moves two or more ions in the same direction.

<span class="mw-page-title-main">Chloride channel</span> Class of transport proteins

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.

Pseudohypoaldosteronism (PHA) is a condition that mimics hypoaldosteronism. Two major types of primary pseudohypoaldosteronism are recognized.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

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.

<span class="mw-page-title-main">OCRL</span> Protein-coding gene in the species Homo sapiens

Inositol polyphosphate 5-phosphatase OCRL-1, also known as Lowe oculocerebrorenal syndrome protein, is an enzyme encoded by the OCRL gene located on the X chromosome in humans.

<span class="mw-page-title-main">LRP2</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 2 also known as LRP-2 or megalin is a protein which in humans is encoded by the LRP2 gene.

<span class="mw-page-title-main">CLCN1</span> Protein-coding gene in the species Homo sapiens

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).

<span class="mw-page-title-main">CLCN2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">CLCN7</span> Protein-coding gene in the species Homo sapiens

Chloride channel 7 alpha subunit also known as H+/Cl exchange transporter 7 is a protein that in humans is encoded by the CLCN7 gene. In melanocytic cells this gene is regulated by the Microphthalmia-associated transcription factor.

<span class="mw-page-title-main">CLCNKB</span> Protein-coding gene in the species Homo sapiens

Chloride channel Kb, also known as CLCNKB, is a protein which in humans is encoded by the CLCNKB gene.

<span class="mw-page-title-main">CLCN6</span> Protein-coding gene in the species Homo sapiens

Chloride transport protein 6 is a protein that in humans is encoded by the CLCN6 gene.

<span class="mw-page-title-main">CLCNKA</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">BSND</span> Protein-coding gene in the species Homo sapiens

Bartter syndrome, infantile, with sensorineural deafness (Barttin), also known as BSND, is a human gene which is associated with Bartter syndrome.

<span class="mw-page-title-main">CLIC5</span> Protein-coding gene in the species Homo sapiens

Chloride intracellular channel protein 5 is a protein that in humans is encoded by the CLIC5 gene.

<span class="mw-page-title-main">CBS domain</span>

In molecular biology, the CBS domain is a protein domain found in a range of proteins in all species from bacteria to humans. It was first identified as a conserved sequence region in 1997 and named after cystathionine beta synthase, one of the proteins it is found in. CBS domains are also found in a wide variety of other proteins such as inosine monophosphate dehydrogenase, voltage gated chloride channels and AMP-activated protein kinase (AMPK). CBS domains regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP and ATP, or s-adenosylmethionine.

Fanconi syndrome or Fanconi's syndrome is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity, or by adverse drug reactions. It results in various small molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid. Fanconi syndrome affects the proximal tubules, namely, the proximal convoluted tubule (PCT), which is the first part of the tubule to process fluid after it is filtered through the glomerulus, and the proximal straight tubule, which leads to the descending limb of loop of Henle.

<span class="mw-page-title-main">Oliver Wrong</span>

Professor Oliver Murray Wrong was an eminent academic nephrologist and one of the founders of the speciality in the United Kingdom. From a background as a "salt and water" physician, he made detailed clinical observations and scientifically imaginative connections which were the basis of numerous advances in the molecular biology of the human kidney. Wrong himself contributed to much of the molecular work after his own "retirement". He dictated amendments to his final paper during his final illness in his own teaching hospital, University College Hospital (UCH), London. Though academic in his leanings, he was a compassionate physician who established a warm rapport with patients, a link he regarded as the keystone of his research. He belonged to a generation of idealistic young doctors responsible for the establishment of the UK's National Health Service in the post-War years.

<span class="mw-page-title-main">Rajesh Thakker</span>

Rajesh Vasantlal Thakker is May Professor of Medicine in the Nuffield Department of Clinical Medicine at the University of Oxford and a fellow of Somerville College, Oxford. Thakker is also a Consultant physician at the Churchill Hospital and the John Radcliffe Hospital, Principal investigator (PI) at the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) and was Chairman of the NIHR/MRC Efficacy and Mechanism Evaluation (EME) Board until Spring 2016.

Chloride channel openers refer to a specific category of drugs designed to modulate chloride channels in the human body. Chloride channels are anion-selective channels which are involved in a wide variety of physiological functions and processes such as the regulation of neuroexcitation, transepithelial salt transport, and smooth muscle contraction. Due to their distribution throughout the body, diversity, functionality, and associated pathology, chloride channels represent an ideal target for the development of channel modulating drugs such as chloride channel openers.

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Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.