CLCN5
CLCN5 | |||
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Gene ontology | |||
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Cellular component | |||
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Sources:Amigo / QuickGO |
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Location (UCSC) | Chr X: 49.92 – 50.1 Mb | Chr X: 7.02 – 7.19 Mb | |||||||
PubMed search | [3] | [4] |
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
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
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
Wikidata Q91915081 . |
References
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000004317 – Ensembl, May 2017
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Further reading
- Igarashi T, Hayakawa H, Shiraga H, Kawato H, Yan K, Kawaguchi H, et al. (1995). "Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent's disease in United Kingdom?". Nephron. 69 (3): 242–7. PMID 7753256.
- Scheinman SJ, Pook MA, Wooding C, Pang JT, Frymoyer PA, Thakker RV (June 1993). "Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies". The Journal of Clinical Investigation. 91 (6): 2351–7. PMID 8099916.
- Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, et al. (February 1996). "A common molecular basis for three inherited kidney stone diseases". Nature. 379 (6564): 445–9. S2CID 4364656.
- Fisher SE, van Bakel I, Lloyd SE, Pearce SH, Thakker RV, Craig IW (October 1995). "Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis)". Genomics. 29 (3): 598–606. PMID 8575751.
- Lloyd SE, Pearce SH, Günther W, Kawaguchi H, Igarashi T, Jentsch TJ, et al. (March 1997). "Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5)". The Journal of Clinical Investigation. 99 (5): 967–74. PMID 9062355.
- Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, et al. (June 1997). "Identification of novel human WW domain-containing proteins by cloning of ligand targets". The Journal of Biological Chemistry. 272 (23): 14611–6. PMID 9169421.
- Oudet C, Martin-Coignard D, Pannetier S, Praud E, Champion G, Hanauer A (June 1997). "A second family with XLRH displays the mutation S244L in the CLCN5 gene". Human Genetics. 99 (6): 781–4. S2CID 1930953.
- Lloyd SE, Gunther W, Pearce SH, Thomson A, Bianchi ML, Bosio M, et al. (August 1997). "Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders". Human Molecular Genetics. 6 (8): 1233–9. PMID 9259268.
- Schurman SJ, Norden AG, Scheinman SJ (May 1998). "X-linked recessive nephrolithiasis: presentation and diagnosis in children". The Journal of Pediatrics. 132 (5): 859–62. PMID 9602200.
- Günther W, Lüchow A, Cluzeaud F, Vandewalle A, Jentsch TJ (July 1998). "ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells". Proceedings of the National Academy of Sciences of the United States of America. 95 (14): 8075–80. PMID 9653142.
- Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV (February 1999). "Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease". Human Molecular Genetics. 8 (2): 247–57. PMID 9931332.
- Lamb FS, Clayton GH, Liu BX, Smith RL, Barna TJ, Schutte BC (March 1999). "Expression of CLCN voltage-gated chloride channel genes in human blood vessels". Journal of Molecular and Cellular Cardiology. 31 (3): 657–66. PMID 10198195.
- Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. (December 2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 16899–903. PMID 12477932.
- Moulin P, Igarashi T, Van der Smissen P, Cosyns JP, Verroust P, Thakker RV, et al. (April 2003). "Altered polarity and expression of H+-ATPase without ultrastructural changes in kidneys of Dent's disease patients". Kidney International. 63 (4): 1285–95. PMID 12631345.
- Wu F, Roche P, Christie PT, Loh NY, Reed AA, Esnouf RM, et al. (April 2003). "Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural-functional relationship". Kidney International. 63 (4): 1426–32. PMID 12631358.
- Carballo-Trujillo I, Garcia-Nieto V, Moya-Angeler FJ, Antón-Gamero M, Loris C, Méndez-Alvarez S, et al. (April 2003). "Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease". Nephrology, Dialysis, Transplantation. 18 (4): 717–23. PMID 12637640.
- Ludwig M, Waldegger S, Nuutinen M, Bökenkamp A, Reissinger A, Steckelbroeck S, et al. (2004). "Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent's phenotype in patients without mutations in the short variant". Kidney & Blood Pressure Research. 26 (3): 176–84. S2CID 41532860.
- Hryciw DH, Wang Y, Devuyst O, Pollock CA, Poronnik P, Guggino WB (October 2003). "Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines" (PDF). The Journal of Biological Chemistry. 278 (41): 40169–76. PMID 12904289.
External links
- CLCN5+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human CLCN5 genome location and CLCN5 gene details page in the UCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.