Affinage

Showing CLCN5 — CLC-5 is a alias.

CLCN5

H(+)/Cl(-) exchange transporter 5 · UniProt P51795

Length
816 aa
Mass
90.8 kDa
Annotated
2026-06-09
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLCN5 (ClC-5) is a member of the CLC family of chloride transport proteins that functions as the principal electrogenic 2Cl⁻/H⁺ exchanger of apical endosomes in the renal proximal tubule, where it is essential for receptor-mediated and fluid-phase endocytosis (PMID:7874126, PMID:11099045). Originally identified by positional cloning as the gene deleted in Dent's disease (PMID:7874126), ClC-5 was first shown by heterologous expression to carry strongly outwardly rectifying anion currents with a NO3⁻ > Cl⁻ > Br⁻ > I⁻ selectivity, with permeation governed by residues in transmembrane domains D2 and D3 (PMID:8537381, PMID:9873029). ClC-5 resides in early/recycling endosomes alongside the vacuolar H⁺-ATPase, internalized ligands, and Rab markers (PMID:9653142, PMID:9931332, PMID:9815133), where it supports endosomal acidification both by providing an electrical shunt for the V-ATPase and by directly exchanging luminal Cl⁻ for cytoplasmic H⁺, contributing a bafilomycin-insensitive acidification component (PMID:12548389, PMID:20421284, PMID:27044412). Genetic disruption in mice abolishes apical proximal tubular endocytosis, causing proteinuria, and produces a downstream endocrine cascade in which defective ligand uptake elevates luminal PTH and drives phosphaturia via internalization of NaPi transporters (PMID:11099045, PMID:12548389). Transport mechanism rests on coupled gating glutamates: the gating glutamate E211 senses extracellular protons and is protonated through the proton glutamate E268, coupling H⁺ movement to Cl⁻ exchange (PMID:20513761, PMID:22267722). Surface delivery and trafficking are controlled by ATP binding to the C-terminal CBS domains, which drives a conformational compaction promoting ER exit and biosynthetic maturation (PMID:16686597, PMID:21173145), and by C-terminal interactions with the NHERF2 scaffold, megalin, and the kinesin motor KIF3B (PMID:16601121, PMID:19940036, PMID:22349218). Loss-of-function CLCN5 mutations cause Dent's disease through several distinct mechanisms — ER retention and proteasomal degradation of misfolded protein, defective endosomal targeting, or selective loss of H⁺ coupling that converts ClC-5 into a pure Cl⁻ channel — establishing that impaired endocytosis, not endosomal acidification alone, underlies the disease (PMID:15942052, PMID:19019917, PMID:23566014, PMID:27044412, PMID:29791050).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 1994 High

    Established CLCN5 as a candidate disease gene by linking a novel kidney-expressed CLC family member to genomic deletion in Dent's disease, defining the gene of interest.

    Evidence Positional cloning by YAC/cDNA screening with deletion mapping in patients

    PMID:7874126

    Open questions at the time
    • Did not establish transport function or subcellular localization
    • Mechanism linking gene loss to renal phenotype unknown
  2. 1995 High

    Demonstrated that ClC-5 carries intrinsic anion current, answering whether it is a functional transport protein and defining its ion selectivity.

    Evidence Heterologous expression in Xenopus oocytes with two-electrode voltage clamp

    PMID:8537381

    Open questions at the time
    • Did not resolve whether activity is channel- or exchanger-based
    • Native subcellular site of activity not addressed
  3. 1998 High

    Placed ClC-5 in endosomal compartments alongside the V-ATPase and endocytosed ligands, establishing the cellular context for its function in renal endocytosis.

    Evidence Immunofluorescence colocalization, rab5 mutant cotransfection, and subcellular fractionation in kidney

    PMID:9653142 PMID:9815133

    Open questions at the time
    • Causal role in acidification not yet tested
    • Whether ClB-5 is required for endocytosis untested
  4. 1999 High

    Mapped permeation-pathway residues (S168, E211) and confirmed plasma-membrane current, providing the first structure-function link for ion handling.

    Evidence Site-directed mutagenesis with two-electrode voltage clamp and HEK293 patch clamp

    PMID:9873029 PMID:9931332

    Open questions at the time
    • Coupling of anion permeation to proton transport not yet defined
    • Endosomal versus surface functional roles unresolved
  5. 2000 High

    Demonstrated genetically that ClC-5 is essential for apical proximal tubular endocytosis and for trafficking of apical transporters, establishing the in vivo pathophysiology.

    Evidence Clcn5 knockout mouse with endocytosis assays and transporter localization

    PMID:11099045

    Open questions at the time
    • Molecular mechanism connecting transport activity to endocytic defect unresolved
    • Direct endosomal pH measurement not yet performed
  6. 2000 High

    Identified a C-terminal PY-like motif controlling surface expression through WWP2-mediated internalization, addressing how ClC-5 trafficking is regulated.

    Evidence PY-motif mutagenesis with dominant-negative WWP2 and electrophysiology in oocytes

    PMID:11116157

    Open questions at the time
    • Physiological relevance not yet tested in vivo (later contradicted)
    • Identity of additional ligases not addressed
  7. 2002 High

    Directly confirmed ClC-5's role in endosomal acidification and traced the cascade to PTH-driven phosphaturia, linking transport to systemic phenotype.

    Evidence Clcn5 KO mouse endosomal acidification assay with hormone measurements

    PMID:12548389

    Open questions at the time
    • Whether ClC-5 itself transports protons or only shunts charge unresolved
    • Quantitative contribution to acidification not partitioned
  8. 2003 Medium

    Showed loss of ClC-5 inverts V-ATPase polarity in patient tubules, indicating a role in maintaining proton-pump distribution.

    Evidence Immunohistochemistry of Dent's disease renal biopsies

    PMID:12631345

    Open questions at the time
    • Single lab, no functional rescue
    • Causality versus secondary effect not established
  9. 2004 High

    Identified Nedd4-2 as a direct C-terminal ubiquitin-ligase partner regulating ClC-5 surface expression and albumin uptake, expanding the trafficking-regulation network.

    Evidence Co-IP, GST pull-down, oocyte electrophysiology, and siRNA albumin uptake assays

    PMID:15489223

    Open questions at the time
    • In vivo requirement of ubiquitylation untested (later contradicted)
    • Relationship to WWP2 pathway unclear
  10. 2005 High

    Demonstrated by rescue that disease mutants fail to restore endocytosis due to defective targeting, mechanistically linking specific mutations to functional loss.

    Evidence Adenoviral re-expression of WT and mutant ClC-5 in KO proximal tubule cells with endocytosis and biotinylation assays

    PMID:15942052

    Open questions at the time
    • Structural basis of mistargeting not resolved
    • Not all mutation classes covered
  11. 2005 High

    Identified NHERF2 (but not NHERF1) as a PDZ-domain scaffold that promotes ClC-5 surface retention and endocytosis, defining a scaffolding control point.

    Evidence Co-IP, GST pull-down, and siRNA with surface biotinylation and albumin uptake assays in OK cells

    PMID:16601121

    Open questions at the time
    • In vivo relevance not established
    • Opposing NHERF1/NHERF2 mechanism not fully resolved
  12. 2006 High

    Showed the C-terminal CBS-containing domain directly binds ATP and is stabilized by it, identifying a nucleotide-sensing regulatory module.

    Evidence Radiolabeled ATP binding, CD spectroscopy, and thermal stability with purified C-terminal domain

    PMID:16686597

    Open questions at the time
    • Functional consequence of ATP binding for the full channel not yet defined
    • Physiological ATP-sensitivity range untested
  13. 2008 High

    Classified Dent's disease mutations into three functional/structural categories, providing a framework for genotype-mechanism correlation.

    Evidence Electrophysiology, confocal localization, acidification assays, and homology modeling of seven mutants

    PMID:19019917

    Open questions at the time
    • Atomic structure not available to confirm modeling
    • Class boundaries based on limited mutant set
  14. 2009 High

    Identified KIF3B as a kinesin motor partner driving microtubule-based trafficking of ClC-5 vesicles, defining the cytoskeletal transport mechanism.

    Evidence Yeast two-hybrid, reciprocal co-IP, live-cell imaging, and siRNA endocytosis assays

    PMID:19940036

    Open questions at the time
    • In vivo requirement of KIF3B for ClC-5 function untested
    • Coordination with scaffold/ubiquitin pathways unclear
  15. 2010 High

    Resolved that ClC-5 directly acidifies endosomes as a Cl⁻/H⁺ exchanger, providing a bafilomycin-insensitive acidification component beyond electrical shunting.

    Evidence Whole-cell patch clamp, endosome-targeted pH sensors, transport-dead mutagenesis, and siRNA in proximal tubule cells

    PMID:20421284

    Open questions at the time
    • Quantitative balance of shunt versus direct H⁺ transport not partitioned
    • Stoichiometry under physiological voltages not yet measured
  16. 2010 High

    Overturned the heterologous-expression model of PY-motif ubiquitylation by showing it is dispensable for endocytosis in vivo, refining the regulatory model.

    Evidence PY-motif knock-in mouse with urine, endocytosis, and transporter localization analyses

    PMID:20351103

    Open questions at the time
    • Reason for discrepancy with oocyte/cell studies unresolved
    • Whether ubiquitylation matters under stress conditions untested
  17. 2010 High

    Defined intrinsic voltage sensing and anion-coupled gating, and localized extracellular proton inhibition to gating glutamate E211, dissecting the transport cycle.

    Evidence Gating-current recordings of permeation-deficient mutant, ion substitution, and SCN⁻ uncoupling with pH manipulation

    PMID:20501796 PMID:20513761

    Open questions at the time
    • Atomic-resolution gating-state structures not available
    • Coupling to in-cell endosomal conditions not directly measured
  18. 2010 High

    Showed ATP binding induces clamp-like compaction of the C-terminus that promotes ER exit and maturation, linking nucleotide sensing to biosynthetic trafficking.

    Evidence SAXS, limited proteolysis, Y617A mutagenesis, and trafficking assays in fibroblasts and tubule cells

    PMID:21173145

    Open questions at the time
    • Structure of nucleotide-bound full-length protein unresolved
    • Physiological ATP fluctuations controlling trafficking untested
  19. 2011 High

    Revealed an exocytic role for ClC-5 in NHE3 surface delivery, broadening its function beyond endocytosis.

    Evidence shRNA in OK cells with exocytosis/endocytosis biotinylation, plus two-photon NHE3 activity in KO mice

    PMID:21561868

    Open questions at the time
    • Molecular link between ClC-5 transport and exocytic machinery unknown
    • Generality to other exocytosed cargo untested
  20. 2012 High

    Demonstrated a three-protein ClC-5/megalin/NHERF2 complex, mechanistically connecting ClC-5 to the receptor-endocytosis machinery.

    Evidence GST pull-down, endogenous co-IP from kidney lysate, NHERF2 siRNA, and fusion-protein reconstitution

    PMID:22349218

    Open questions at the time
    • Stoichiometry and dynamics of the complex in vivo unresolved
    • Functional consequence for megalin recycling not directly measured
  21. 2012 High

    Established that proton glutamate E268 mediates protonation of gating glutamate E211, defining the molecular coupling between H⁺ and Cl⁻ transport.

    Evidence Charge-coupled mutagenesis, gating-charge measurements, and sulfhydryl modification

    PMID:22267722

    Open questions at the time
    • Structural confirmation of the protonation pathway absent
    • Behavior at native endosomal pH not directly tested
  22. 2013 High

    Showed specific disease mutants are misfolded and proteasomally degraded, defining a degradation-based disease mechanism for membrane and C-terminal mutations.

    Evidence Limited proteolysis, proteasome inhibition, and polyubiquitination IP in OK cells

    PMID:23566014

    Open questions at the time
    • Quality-control machinery recognizing the mutants unidentified
    • Whether chaperone rescue is feasible untested
  23. 2016 High

    Demonstrated functional coupling between ClC-5 and the V-ATPase, showing a pure-Cl⁻-channel mutant still causes disease via insufficient V-ATPase activation.

    Evidence Oocyte electrophysiology, surface pH, and V-ATPase activation assays in cells and native tubules

    PMID:27044412

    Open questions at the time
    • Mechanism of physical/functional V-ATPase coupling unresolved
    • Relative contribution of H⁺ coupling versus charge shunt in vivo unquantified
  24. 2018 High

    Showed a gating-glutamate mutant that preserves trafficking and endosomal pH yet causes disease, establishing that impaired acidification is not the sole disease mechanism.

    Evidence Oocyte and HEK293T electrophysiology, glycosylation/localization analysis, and pHluorin2 endosomal pH measurement

    PMID:29791050

    Open questions at the time
    • Alternative disease-causing function of Cl⁻/H⁺ exchange unidentified
    • In vivo phenotype of this variant untested
  25. 2019 High

    Measured native 2Cl⁻/H⁺ stoichiometry and showed variant-specific alterations in transport and trafficking, refining the quantitative transport model.

    Evidence Ion-selective microelectrodes in oocytes and organelle-probe localization with surface-expression assays for multiple variants

    PMID:31852738

    Open questions at the time
    • Burst-mode acidification model not validated in native endosomes
    • Variant phenotypes not tested in animal models

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ClC-5's Cl⁻/H⁺ exchange activity is mechanistically coupled to endocytic and exocytic membrane trafficking — beyond endosomal acidification — remains undefined.
  • No atomic structure of full-length human ClC-5 in the corpus
  • Direct molecular link between transport activity and cargo trafficking machinery unresolved
  • Non-acidification disease mechanism unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140657 ATP-dependent activity 2
Localization
GO:0005768 endosome 4 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
KIF3BLRP2NEDD4LNHERF2WWP2

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CLCN5 (initially termed hCIC-K2) was identified as a novel member of the CLC family of voltage-gated chloride channels, expressed predominantly in the kidney, with its genomic region completely deleted in Dent's disease patients, establishing it as the candidate disease gene. Positional cloning using YAC screening of kidney cDNA library; evolutionary conservation analysis; deletion mapping Human molecular genetics High 7874126
1995 Heterologous expression of rat CLC-5 in Xenopus oocytes elicits novel, strongly outwardly rectifying anion currents with conductivity sequence NO3- > Cl- > Br- > I- >> glutamate-, establishing direct chloride channel activity; cAMP had no effect on these currents. Xenopus oocyte expression system with two-electrode voltage clamp; pharmacological manipulation of cAMP The Journal of biological chemistry High 8537381
1998 ClC-5 colocalizes with the vacuolar H+-ATPase (proton pump) and with internalized proteins in endocytotically active renal proximal tubule cells and alpha-intercalated cells, and in transfected cells colocalizes with endocytosed alpha2-macroglobulin and enlarges rab5-Q79L early endosomes, suggesting ClC-5 resides in early endosomes and provides an electrical shunt for endosomal acidification. Immunofluorescence colocalization; cotransfection with GTPase-deficient rab5 mutant; endosome tracking with labeled ligands Proceedings of the National Academy of Sciences of the United States of America High 9653142
1999 Active-site mutagenesis of ClC-5 demonstrated that point mutations at the end of transmembrane domain D2 (S168T) change ion selectivity, and a mutation at D3 (E211A) changes voltage dependence and ion selectivity, directly establishing that ClC-4 and ClC-5 mediate plasma membrane currents and that these residues contribute to the ion permeation pathway. Site-directed mutagenesis; two-electrode voltage clamp in Xenopus oocytes and patch-clamp in HEK293 cells The Journal of biological chemistry High 9873029
1999 Human CLC-5 is co-distributed with Rab4 (a recycling early endosome marker) in subcellular fractions of human kidney cortex, and colocalizes with albumin-containing endocytic vesicles in opossum kidney proximal tubule cells, placing CLC-5 in the receptor-mediated endocytic pathway. Subcellular fractionation; immunoblotting; confocal immunofluorescence microscopy with albumin endocytosis tracking Human molecular genetics High 9931332
2000 Disruption of the mouse clcn5 gene causes proteinuria by strongly reducing apical proximal tubular endocytosis (both receptor-mediated and fluid-phase), establishing ClC-5 as essential for renal endocytosis; additionally, internalization of apical transporters NaPi-2 and NHE3 is slowed. Clcn5 knockout mouse; endocytosis assays with labeled tracers; immunohistochemistry and subcellular fractionation of NaPi-2 and NHE3 Nature High 11099045
2000 A carboxyl-terminal PY-like motif in ClC-5 mediates its internalization from the plasma membrane via interaction with WW domain-containing ubiquitin-protein ligase WWP2; mutation of this motif increases surface expression and currents ~2-fold, and dominant-negative WWP2 increases surface ClC-5 only when the PY motif is intact. Site-directed mutagenesis of PY motif; dominant-negative expression of WWP2; rab5 overexpression/dominant-negative studies; electrophysiology in Xenopus oocytes The Journal of biological chemistry High 11116157
2002 Endosomes from Clcn5 knockout mice are acidified at a significantly lower rate than wild-type endosomes, confirming that ClC-5 provides an electrical shunt for efficient vacuolar H+-ATPase operation; defective endocytosis leads to elevated luminal PTH, causing increased endocytosis of NaPi phosphate transporter and phosphaturia. Clcn5 KO mouse; endosomal acidification assay; hormone level measurements; immunohistochemistry of NaPi Pflugers Archiv : European journal of physiology High 12548389
2003 Loss of CLC-5 in Dent's disease patients is associated with inversion of H+-ATPase polarity in proximal tubule cells (basolateral rather than apical) without ultrastructural changes, demonstrating that CLC-5 is required to maintain proper H+-ATPase polarity. Immunohistochemistry of renal biopsies from Dent's disease patients; confocal microscopy Kidney international Medium 12631345
2004 Nedd4-2 interacts with ClC-5 via a direct binding of the C-terminus of ClC-5 to Nedd4-2; Nedd4-2 decreases cell surface expression of ClC-5 in Xenopus oocytes; albumin stimulates ubiquitination of ClC-5 and increases its surface expression; knockdown of Nedd4-2 by siRNA reduces albumin uptake in proximal tubule cells. In vivo co-immunoprecipitation; GST pull-down; Xenopus oocyte electrophysiology; siRNA knockdown; albumin endocytosis assay The Journal of biological chemistry High 15489223
2005 Adenoviral re-expression of wild-type ClC-5 rescues receptor-mediated endocytosis in ClC-5 KO proximal tubule cells, whereas disease-causing mutants (W22G, S520P, R704X) do not rescue endocytosis; S520P and R704X are not internalized normally, suggesting defective targeting/trafficking underlies Dent's disease in these cases. Adenoviral transduction of KO primary proximal tubule cells; endocytosis assay; surface biotinylation; electrophysiology American journal of physiology. Renal physiology High 15942052
2005 ClC-5 has an internal C-terminal binding site that directly interacts with the PDZ2 domain of NHERF2 (but not NHERF1); silencing NHERF2 reduces cell-surface ClC-5 and albumin uptake, whereas silencing NHERF1 increases ClC-5 surface levels and albumin endocytosis. Co-immunoprecipitation from OK cell lysate; GST fusion protein pull-down; siRNA knockdown; surface biotinylation; albumin endocytosis assay The Journal of biological chemistry High 16601121
2006 The C-terminus of ClC-5 (containing CBS domains) directly binds ATP with low millimolar affinity; ATP and AMP binding induces no change in secondary structure but increases thermal stability of the C-terminal domain. Radiolabeled ATP binding assay; circular dichroism (CD) spectroscopy; thermal stability measurements with purified recombinant C-terminal domain The Biochemical journal High 16686597
2008 CLC-5 mutations causing Dent's disease fall into three functional classes: Class 1 mutations cause ER retention and degradation; Class 2 mutations allow normal trafficking but abolish endosomal acidification; Class 3 mutations alter endosomal distribution but preserve acidification. Molecular modeling showed each class maps to discrete structural regions. Electrophysiology; subcellular localization by confocal microscopy; endosomal acidification assay; 3D homology modeling of seven missense mutants American journal of physiology. Renal physiology High 19019917
2009 CLC-5 interacts with the kinesin motor protein KIF3B via the C-terminus of CLC-5 and the coiled-coil/globular domains of KIF3B; KIF3B overexpression increases and KIF3B siRNA knockdown decreases CLC-5 surface expression and albumin/transferrin endocytosis; CLC-5-containing vesicles move along KIF3B microtubules in live kidney cells. Yeast two-hybrid; GST pull-down; co-immunoprecipitation (including endogenous); confocal live-cell imaging; siRNA knockdown; endocytosis assay American journal of physiology. Renal physiology High 19940036
2010 CLC-5 directly acidifies endosomes by exchanging endosomal Cl- for H+ from the cytoplasm (acting as a Cl-/H+ exchanger), providing a bafilomycin-insensitive component of endosomal acidification; mutations that remove H+ transport (E268A, E211A) abolish this additional acidification. siRNA knockdown of endogenous CLC-5 in proximal tubule cells nearly fully ablated bafilomycin-insensitive acidification. Whole-cell patch clamp; pH-sensitive fluorescent protein targeted to endosomes; site-directed mutagenesis (E268A, E211A); siRNA knockdown; bafilomycin inhibition The Journal of physiology High 20421284
2010 ClC-5 PY-motif-dependent ubiquitylation is dispensable for proximal tubular endocytosis in vivo: knock-in mice with a destroyed PY-motif show neither proteinuria nor hyperphosphaturia, and receptor-mediated and fluid-phase endocytosis are normal, contradicting results from heterologous expression systems. PY-motif knock-in mouse; urine protein analysis; endocytosis assays; megalin and NaPi-2a localization by immunohistochemistry The Journal of biological chemistry High 20351103
2010 CLC-5 voltage sensing is an intrinsic property of the protein; permeant anions (particularly Cl-) modulate a voltage-dependent transition to an activated state from which Cl-/H+ exchange occurs. Intracellular Cl- shifts the charge-voltage relationship while lowering intracellular pH does not shift voltage dependence of gating currents. Whole-cell patch clamp of E268A permeation-deficient mutant; gating current recordings; ion substitution experiments FASEB journal : official publication of the Federation of American Societies for Experimental Biology High 20501796
2010 Extracellular protons inhibit CLC-5 by binding to a single site at the extracellular gating glutamate E211, located halfway through the transmembrane electric field, driving the transport cycle in a less permissive direction rather than by reducing driving force. Electrophysiology with varying extracellular pH; SCN- uncoupling experiments to separate H+ and Cl- transport; mechanistic transport cycle modeling The Journal of general physiology High 20513761
2010 ATP binding induces a conformational change (clamp-like closure) in the isolated C-terminal region of ClC-5, as shown by small-angle X-ray scattering; this conformational compaction promotes biosynthetic maturation and ER exit of full-length ClC-5. Disruption of the ATP-binding site (Y617A) impairs processing and ER trafficking. Small-angle X-ray scattering (SAXS); limited proteolysis; site-directed mutagenesis (Y617A); trafficking assay in fibroblasts and proximal tubule cells The Journal of biological chemistry High 21173145
2011 ClC-5 is required for exocytic trafficking of NHE3: ClC-5 knockdown reduces basal and dexamethasone-stimulated NHE3 exocytosis (but not endocytosis) in opossum kidney cells, and NHE3 activity is reduced in proximal tubules of Clcn5 KO mice. shRNA knockdown in OK cells; surface biotinylation exocytosis/endocytosis assays; two-photon microscopy of NHE3 activity in Clcn5 KO mice; single tubule perfusion The Journal of biological chemistry High 21561868
2012 ClC-5 and megalin interact via their C-termini, and this interaction is scaffolded by NHERF2: GST pull-down and co-immunoprecipitation in rat kidney lysate demonstrated the ClC-5/megalin complex; silencing NHERF2 disrupts the megalin/ClC-5 interaction. Fusion protein reconstitution demonstrated a three-protein complex of ClC-5, megalin, and NHERF2. GST pull-down; co-immunoprecipitation from rat kidney lysate; siRNA knockdown of NHERF2; fusion protein reconstitution The international journal of biochemistry & cell biology High 22349218
2012 The proton glutamate E268 of ClC-5 mediates protonation of gating glutamate E211: internal protons increase transport probability of ClC-5 via protonation of E211 at the central anion-binding site, and this effect requires E268. Sulfhydryl modification of E268C mutant confirmed the charge-dependent mechanism. Site-directed mutagenesis (E268H, E268C, E211C, S168P); gating charge measurements; site-directed sulfhydryl modification; electrophysiology The Journal of biological chemistry High 22267722
2013 Disease-causing ClC-5 mutants C221R (membrane domain) and R718X (C-terminal truncation) are misfolded: limited proteolysis shows enhanced protease susceptibility relative to wild-type. C221R disrupts intramolecular interactions affecting the N-terminal cytosolic region; R718X perturbs both C-terminal and membrane domains. Both misfolded mutants are polyubiquitinated and degraded by the proteasome in renal proximal tubule cells. Limited proteolysis; proteasome inhibition assay; polyubiquitination immunoprecipitation in OK cells; protein stability assays The Biochemical journal High 23566014
2016 The gating glutamate E211Q mutation converts ClC-5 from a 2Cl-/H+ exchanger into a pure Cl- channel, which still causes Dent's disease in humans via insufficient V-ATPase activation; both E211A and E211Q stimulate endosomal acidification and V-ATPase activation but less effectively than WT ClC-5, demonstrating functional coupling between V-ATPase and CLC-5. Xenopus oocyte electrophysiology; surface pH measurement; V-ATPase activation assay in HEK293 cells and isolated mouse proximal tubules; gene silencing Pflugers Archiv : European journal of physiology High 27044412
2018 A novel gating glutamate mutation p.Glu211Gly converts ClC-5 to a Cl- channel (abolishes outward rectification, pH sensitivity, and Cl-/H+ exchange) but does not impair N-glycosylation, plasma membrane localization, or endosomal localization, and does not significantly alter luminal endosomal pH in HEK293T cells, demonstrating that impaired endosomal acidification is not the sole mechanism of Dent's disease. Xenopus oocyte electrophysiology; HEK293T cell expression; N-glycosylation analysis; subcellular localization; pHluorin2 endosomal pH measurement Human mutation High 29791050
2019 WT ClC-5 has a 2Cl-/H+ exchange stoichiometry at +40 mV; the S244L variant shows altered stoichiometry (~1.6:1) and reduced Cl-/H+ transport; R345W has slightly higher transport than S244L but is retained in early endosomes; Q629* is retained in ER/cis-Golgi and shows minimal transport. ClC-5 transport is self-inhibitory (provides net negative charges) but facilitates H+-ATPase-mediated endosomal acidification in a burst mode. Ion-selective microelectrodes in Xenopus oocytes; eGFP-tagged protein localization with organelle probes in HEK293 cells; chemiluminescent surface expression assay The Journal of biological chemistry High 31852738
1998 ClC-5 protein is localized to intracellular endosomal compartments (outer medullary endosomes) in the S3 segment of the proximal tubule and medullary thick ascending limb of rat kidney, as established by isoform-specific antiserum and subcellular membrane fractionation. Subcellular membrane fractionation; flow cytometry; immunohistochemistry with isoform-specific antibody; in situ hybridization The American journal of physiology High 9815133

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 435 11099045
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 362 9653142
1999 Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Human molecular genetics 241 9931332
1995 Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease. The Journal of biological chemistry 239 8537381
1999 Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents. The Journal of biological chemistry 209 9873029
2010 Dent's disease. Orphanet journal of rare diseases 170 20946626
2002 The ClC-5 chloride channel knock-out mouse - an animal model for Dent's disease. Pflugers Archiv : European journal of physiology 159 12548389
1997 Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Human molecular genetics 135 9259268
1994 Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). Human molecular genetics 135 7874126
1995 Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics 125 8575751
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 121 9062355
2000 An internalization signal in ClC-5, an endosomal Cl-channel mutated in dent's disease. The Journal of biological chemistry 114 11116157
2004 Evidence for genetic heterogeneity in Dent's disease. Kidney international 89 15086899
2000 Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases. Kidney international 87 10620205
2010 Dent's disease: clinical features and molecular basis. Pediatric nephrology (Berlin, Germany) 79 20936522
2000 Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis. Kidney international 78 10720930
2015 Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1. Human mutation 77 25907713
2004 Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. The Journal of biological chemistry 75 15489223
2003 Altered polarity and expression of H+-ATPase without ultrastructural changes in kidneys of Dent's disease patients. Kidney international 67 12631345
1998 Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease. Kidney international 67 9853249
2002 Responsiveness of hypercalciuria to thiazide in Dent's disease. Journal of the American Society of Nephrology : JASN 65 12444212
1997 Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. Kidney international 64 9328929
2012 Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. Journal of human genetics 63 22695891
1998 CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis. Kidney international 56 9734595
1998 Intrarenal and subcellular localization of rat CLC5. The American journal of physiology 56 9815133
1999 Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proceedings of the National Academy of Sciences of the United States of America 55 10518595
2006 Phenotypic and genetic heterogeneity in Dent's disease--the results of an Italian collaborative study. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 52 16822791
1998 Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. Journal of the American Society of Nephrology : JASN 52 9596078
2009 CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. American journal of physiology. Renal physiology 51 19940036
2005 ClC-5: role in endocytosis in the proximal tubule. American journal of physiology. Renal physiology 51 15942052
2008 Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. American journal of physiology. Renal physiology 49 19019917
2006 Regulation of albumin endocytosis by PSD95/Dlg/ZO-1 (PDZ) scaffolds. Interaction of Na+-H+ exchange regulatory factor-2 with ClC-5. The Journal of biological chemistry 49 16601121
2011 ClC-5 mutations associated with Dent's disease: a major role of the dimer interface. Pflugers Archiv : European journal of physiology 47 22083641
2005 Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization. Human genetics 47 15895257
2000 Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney international 47 10620204
2000 Characterization of renal chloride channel (CLCN5) mutations in Dent's disease. Journal of the American Society of Nephrology : JASN 47 10906159
2015 IL-4 Up-Regulates MiR-21 and the MiRNAs Hosted in the CLCN5 Gene in Chronic Lymphocytic Leukemia. PloS one 46 25909590
1999 Comparison of amphibian and human ClC-5: similarity of functional properties and inhibition by external pH. The Journal of membrane biology 42 10191359
2010 Role of ClC-5 in renal endocytosis is unique among ClC exchangers and does not require PY-motif-dependent ubiquitylation. The Journal of biological chemistry 41 20351103
2005 ClC-5: a chloride channel with multiple roles in renal tubular albumin uptake. The international journal of biochemistry & cell biology 40 16226913
2010 Direct endosomal acidification by the outwardly rectifying CLC-5 Cl(-)/H(+) exchanger. The Journal of physiology 39 20421284
2010 Voltage-dependent charge movement associated with activation of the CLC-5 2Cl-/1H+ exchanger. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 20501796
2009 Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney international 39 19657328
2006 Hypercalciuria in patients with CLCN5 mutations. Pediatric nephrology (Berlin, Germany) 39 16807762
2000 Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease. Kidney international 39 10916075
1997 Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria. Kidney international 39 9328927
2012 Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies. PloS one 35 23029130
2010 A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency. Pediatric nephrology (Berlin, Germany) 34 20680351
1998 CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. Kidney international 34 9452997
2020 From protein uptake to Dent disease: An overview of the CLCN5 gene. Gene 33 32289351
2015 Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations. SpringerPlus 33 26389017
2005 Chloride channels and endocytosis: new insights from Dent's disease and ClC-5 knockout mice. Nephron. Physiology 33 15637424
2003 Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 33 12637640
2001 Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent's disease). American journal of kidney diseases : the official journal of the National Kidney Foundation 31 11136179
2010 Cadmium impairs albumin reabsorption by down-regulating megalin and ClC5 channels in renal proximal tubule cells. Environmental health perspectives 30 20576581
2005 The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping. Journal of human genetics 30 16041495
2003 De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent's disease. Human genetics 30 14569459
1999 Renal chloride channel, CLCN5, mutations in Dent's disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29 10469281
2009 Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease. Nephron. Physiology 28 19546591
2008 Transcriptional adaptation to Clcn5 knockout in proximal tubules of mouse kidney. Physiological genomics 27 18349385
2011 Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Human mutation 26 21305656
2011 A patient with Dent disease and features of Bartter syndrome caused by a novel mutation of CLCN5. European journal of pediatrics 26 21932010
2009 Locus heterogeneity of Dent's disease: OCRL1 and TMEM27 genes in patients with no CLCN5 mutations. Pediatric nephrology (Berlin, Germany) 26 19582483
1997 A second family with XLRH displays the mutation S244L in the CLCN5 gene. Human genetics 26 9187673
2014 ClC-5: Physiological role and biophysical mechanisms. Cell calcium 25 25443653
2012 The interaction between megalin and ClC-5 is scaffolded by the Na⁺-H⁺ exchanger regulatory factor 2 (NHERF2) in proximal tubule cells. The international journal of biochemistry & cell biology 25 22349218
2018 A Novel CLCN5 Mutation Associated With Focal Segmental Glomerulosclerosis and Podocyte Injury. Kidney international reports 24 30426109
2017 Mutational analysis of PHEX, FGF23 and CLCN5 in patients with hypophosphataemic rickets. Clinical endocrinology 24 28383812
2010 Proton block of the CLC-5 Cl-/H+ exchanger. The Journal of general physiology 23 20513761
2001 Expression of chloride channel, ClC-5, and its role in receptor-mediated endocytosis of albumin in OK cells. Biochemical and biophysical research communications 23 11263994
2012 An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes. European journal of human genetics : EJHG 22 23047739
2006 Nucleotides bind to the C-terminus of ClC-5. The Biochemical journal 22 16686597
2004 Expression and roles of Cl- channel ClC-5 in cell cycles of myeloid cells. Biochemical and biophysical research communications 22 15047167
1999 Chloride channel CLCN5 mutations in Japanese children with familial idiopathic low molecular weight proteinuria. Kidney international 22 9893114
2023 The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype. Kidney international reports 21 37284679
2018 A novel CLCN5 pathogenic mutation supports Dent disease with normal endosomal acidification. Human mutation 21 29791050
2017 Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR. Physiological reports 21 28676554
2007 Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic machinery in Dent's disease. Nephron. Physiology 21 18025833
2004 Comparative ontogeny, processing, and segmental distribution of the renal chloride channel, ClC-5. Kidney international 21 14675051
2003 Coexpression of complementary fragments of ClC-5 and restoration of chloride channel function in a Dent's disease mutation. American journal of physiology. Cell physiology 21 13679301
2017 ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy. Oncology research 20 28899456
2013 Conformational defects underlie proteasomal degradation of Dent's disease-causing mutants of ClC-5. The Biochemical journal 20 23566014
2012 Glutamate 268 regulates transport probability of the anion/proton exchanger ClC-5. The Journal of biological chemistry 20 22267722
2011 Chloride channel (Clc)-5 is necessary for exocytic trafficking of Na+/H+ exchanger 3 (NHE3). The Journal of biological chemistry 19 21561868
2011 Decreased renal accumulation of aminoglycoside reflects defective receptor-mediated endocytosis in cystic fibrosis and Dent's disease. Pflugers Archiv : European journal of physiology 19 21927812
2010 Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis. Journal of immunology (Baltimore, Md. : 1950) 19 20181886
2020 Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies. International journal of molecular sciences 18 31947599
2016 A pure chloride channel mutant of CLC-5 causes Dent's disease via insufficient V-ATPase activation. Pflugers Archiv : European journal of physiology 18 27044412
2005 Phenotype and genotype of Dent's disease in three Korean boys. Pediatric nephrology (Berlin, Germany) 18 15719255
2023 Clinical and genetic characteristics of Dent's disease type 1 in Europe. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 16 36441012
2019 Cl- and H+ coupling properties and subcellular localizations of wildtype and disease-associated variants of the voltage-gated Cl-/H+ exchanger ClC-5. The Journal of biological chemistry 16 31852738
2016 Functional and transport analyses of CLCN5 genetic changes identified in Dent disease patients. Physiological reports 16 27117801
2010 ClC transporters: discoveries and challenges in defining the mechanisms underlying function and regulation of ClC-5. Pflugers Archiv : European journal of physiology 16 20049483
2010 ATP induces conformational changes in the carboxyl-terminal region of ClC-5. The Journal of biological chemistry 16 21173145
2009 ClC-5 regulates dentin development through TGF-beta1 pathway. Archives of oral biology 16 19878925
2007 A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent's disease. Journal of human genetics 16 17262170
2003 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 16 12886045
2003 Identification of a novel splice site mutation of CLCN5 gene and characterization of a new alternative 5' UTR end of ClC-5 mRNA in human renal tissue and leukocytes. Journal of human genetics 16 14673707
2020 Functional analysis of suspected splicing variants in CLCN5 gene in Dent disease 1. Clinical and experimental nephrology 15 32201916
2019 Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts. Pediatric nephrology (Berlin, Germany) 15 30852663

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