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CLCN5

This article was updated by an external expert under a dual publication model. The corresponding peer-reviewed article was published in the journal Gene. Click to view.
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CLCN5
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCLCN5,CLC5, CLCK2, ClC-5, DENTS, NPHL1, NPHL2, XLRH, XRN, hCIC-K2, chloride voltage-gated channel 5, DENT1
External IDsOMIM:300008;MGI:99486;HomoloGene:73872;GeneCards:CLCN5;OMA:CLCN5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1184

12728

Ensembl

ENSG00000171365

ENSMUSG00000004317

UniProt

P51795

Q9WVD4

RefSeq (mRNA)

NM_000084
NM_001127898
NM_001127899
NM_001272102
NM_001282163

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 MbChr X: 7.02 – 7.19 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TheCLCN5geneencodes thechloride channelCl-/H+ exchanger ClC-5. ClC-5 is mainly expressed in thekidney,in particular inproximal tubuleswhere it participates to the uptake ofalbuminand low-molecular-weight proteins, which is one of the principal physiological role of proximal tubular cells.Mutationsin theCLCN5gene cause anX-linked recessivenephropathy namedDent 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) andnephrolithiasis(kidney stones).

The CLCN5 gene[edit]

Structure[edit]

The humanCLCN5gene (MIM#300008, reference sequence NG_007159.2) is localized in the pericentromeric region onchromosomeXp11.23. It extends over about 170 Kb ofgenomic DNA,has a coding region of 2,238 bp and consists of 17exonsincluding 11 coding exons (from 2 to 12).[5][6][7][8]TheCLCN5gene has 8paralogues(CLCN1,CLCN2,CLCN3,CLCN4,CLCN6,CLCN7,CLCNKA,CLCNKB) and 201orthologuesamong jawed vertebrates (Gnathostomata).

Five differentCLCN5gene transcriptshave been discovered, two of which (transcript variants 3 [NM_000084.5] and 4 [NM_001282163.1]) encode for the canonical 746 amino acidprotein,two (transcript variants 1 [NM_001127899.3] and 2 [NM_001127898.3]) for theNH2-terminalextended 816 amino acid protein[9]and one does not encode for any protein (Transcript variant 5, [NM_001272102.2]). The5’ untranslated region(5’UTR) ofCLCN5is complex and not entirely clarified. Two strong and one weakpromoterswere predicted to be present in theCLCN5gene.[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 differentmRNAs,with transcription initiating from at least three different start sites.[10]

The chloride channel H+/Cl−exchanger ClC-5[edit]

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-dimersdue to its marked sequence homology withClC-3andClC-4.[16][17][18]

The canonical 746-amino acidClC-5 protein has 18membranespanningα-helices(named A to R), an intracellular N- terminaldomainand a cytoplasmic C-terminus containing twocystathionine 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 theglutamic acidsat 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[edit]

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

ClC-5 is expressed in minor to moderate level inbrain,muscle,intestinebut highly in the kidney, primarily in proximal tubular cells of S3 segment, in alfa intercalated cells of corticalcollecting ductof and in cortical and medullary thick ascending limb ofHenle’s loop.[33][34][35][36][37][38]

Proximal tubular cells (PTCs) are the main site of ClC-5 expression. By means of thereceptor-mediated endocytosisprocess, they uptake albumin and low-molecular-weight proteins freely passed through theglomerular filter.ClC-5 is located in earlyendosomesof 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 acidicpH.Environment acidification is necessary for the dissociation ofligandfrom itsreceptor.The receptor is then recycled to the apical membrane, while ligand is transported to the late endosome andlysosomewhere 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 involvesmegalinandcubilin/amnionlessreceptors, the sodium-hydrogen antiporter 3 (NHE3), and the V-ATPase.[41][42]It was demonstrated at the C-terminus of ClC-5 binds theactin-depolymerizing proteincofilin.When the nascent endosome forms, the recruitment of cofilin by ClC-5 is a prerequisite for the localized dissolution of the actincytoskeleton,thus permitting the endosome to pass into thecytoplasm.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[edit]

Dent diseaseis mainly caused byloss-of-functionmutations in theCLCN5gene (Dent disease 1; MIM#300009).[14][43]Dent disease 1 shows a markedallelic heterogeneity.To date, 265 differentCLCN5pathogenic 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,frameshiftor complex), 37% non-truncating (missenseor in-frameinsertions/deletions), 10%splice site mutations,and 5% other type (large deletions,Aluinsertions or 5’UTR mutations). Functional investigations inXenopus laevisoocytesand mammalian cells[39][43][45][46][47][40]enabled theseCLCN5mutations to be classified according to their functional consequences.[8][44][48][49][50]The most common mutations lead to a defectiveprotein foldingandprocessing,resulting inendoplasmic reticulumretention of the mutant protein for further degradation by theproteasome.

Animal models[edit]

Two independent ClC-5knock-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-weightproteinuria,hypercalciuriaandnephrocalcinosis/nephrolithiasis) and demonstrated that ClC-5 inactivation is associated with severe impairment of both fluid phase andreceptor-mediated endocytosis,as well astraffickingdefects leading to the loss ofmegalinandcubilinat thebrush borderof proximal tubules. However, targeted disruption of ClC-5 in the Jentsch model did not lead tohypercalciuria,kidney stonesornephrocalcinosis,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 cotransporterNaPi2athat 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[edit]

A clinical diagnosis of Dent disease can be confirmed through moleculargenetic testingthat 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 ofhealthy carrierin the mother of an affected male. In fact, being Dent disease anX-linked recessive disorder,males are more frequently affected than females, and females may beheterozygoushealthy carrier. Due toskewed X-inactivation,female carriers may present some mild symptoms of Dent disease such as low-molecular-weightproteinuriaorhypercalciuria.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 passY chromosometo males, but all their daughters will inherited mutatedX chromosome.Preimplantandprenatal genetic testingis not advised for Dent disease 1 since the prognosis for the majority of the patients is good and a clear correlation betweengenotypeandphenotypeis lacking.[57]

See also[edit]

Notes[edit]

References[edit]

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