Affinage

CLCN5

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

Length
816 aa
Mass
90.8 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLCN5 encodes ClC-5, an electrogenic 2Cl⁻/1H⁺ antiporter predominantly localized to early endosomes of renal proximal tubule cells, where it provides an electrical shunt for the vacuolar H⁺-ATPase to drive endosomal acidification and support receptor-mediated endocytosis (PMID:16034421, PMID:19131966, PMID:9931332, PMID:12548389). ClC-5 transport activity is regulated by intracellular protons and by ATP/ADP binding to its cytoplasmic CBS domains; its C-terminus physically interacts with cofilin, KIF3B, and a megalin–NHERF2 scaffold complex, coupling vesicle trafficking, actin dynamics, and endocytic receptor positioning (PMID:17195847, PMID:12904289, PMID:19940036, PMID:22349218). Loss of ClC-5 in knockout mice causes defective trafficking of the endocytic receptors megalin and cubilin, severely impairing proximal tubular uptake of low-molecular-weight proteins and producing proteinuria, aminoaciduria, hypercalciuria, and disordered vitamin D metabolism characteristic of Dent disease (PMID:11115837, PMID:12815097, PMID:16672909). Dent disease–causing CLCN5 mutations act through distinct mechanisms: some abolish ion transport while preserving trafficking, and others cause ER retention due to protein misfolding, while conversion to a pure Cl⁻ channel (E211G) demonstrates that the coupled H⁺ transport mode itself is required for normal endocytosis beyond simple acidification (PMID:19657328, PMID:29791050).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    The first demonstration that ClC-5 encodes a functional ion-conducting protein established it as a kidney-expressed chloride transporter with strong outward rectification, opening the question of its physiological role.

    Evidence Heterologous expression of rat ClC-5 in Xenopus oocytes with two-electrode voltage clamp

    PMID:8537381

    Open questions at the time
    • Transport vs. channel mechanism unresolved
    • Subcellular localization unknown
    • No link to disease pathophysiology yet
  2. 1999 High

    Localization of ClC-5 to Rab4-positive early endosomes in proximal tubule cells and mutagenesis identifying key pore residues (S168, E211) redirected the field from plasma-membrane channel models toward an endosomal function.

    Evidence Subcellular fractionation of human kidney with immunoblotting; confocal co-localization; site-directed mutagenesis with electrophysiology in oocytes and HEK293 cells

    PMID:9873029 PMID:9931332

    Open questions at the time
    • Functional consequence of endosomal localization not yet demonstrated
    • Whether endosomal acidification depends on ClC-5 untested
  3. 2000 High

    ClC-5 knockout mice recapitulated the Dent disease phenotype — low-molecular-weight proteinuria, aminoaciduria, and impaired proximal tubular endocytosis — establishing ClC-5 as essential for renal endocytic uptake in vivo.

    Evidence Targeted gene disruption in mice with HRP endocytosis assay and urinary biochemistry

    PMID:11115837

    Open questions at the time
    • Molecular mechanism linking ClC-5 loss to endocytic failure unknown
    • Whether endosomal acidification is the primary defect unresolved
  4. 2002 High

    Endosomes from ClC-5 KO mice acidified more slowly than wild-type, directly demonstrating that ClC-5 provides a counter-ion conductance that facilitates H⁺-ATPase-driven acidification, and linking defective acidification to impaired PTH clearance and downstream phosphaturia.

    Evidence Endosomal acidification assay in KO vs. WT mice; PTH receptor and vitamin D pathway measurements

    PMID:12548389

    Open questions at the time
    • Whether ClC-5 functions as a channel or antiporter still unknown
    • Relative contributions of acidification defect vs. other trafficking defects unclear
  5. 2003 High

    Multiple studies converged to show that ClC-5 loss causes selective mistrafficking of megalin and cubilin from the brush border, that its C-terminus interacts with cofilin to regulate actin dynamics during endocytosis, and that disease mutations disrupting CBS domain 2 prevent endosomal targeting — revealing that ClC-5 has both ion-transport and protein-scaffolding roles.

    Evidence ClC-5 KO mice with immunogold labeling and Percoll fractionation; yeast two-hybrid and GST pulldown for cofilin; confocal localization of CBS-truncation mutants; patient renal biopsies

    PMID:12631345 PMID:12815097 PMID:12904289 PMID:14521953

    Open questions at the time
    • Whether cofilin interaction is direct in vivo or mediated by other factors
    • Structural basis of CBS domain role in trafficking unknown
    • Whether H⁺-ATPase mislocalization in patients is cause or consequence
  6. 2005 High

    The paradigm-shifting discovery that ClC-5 is a Cl⁻/H⁺ antiporter — not a passive Cl⁻ channel — fundamentally redefined its mechanism: it actively transports protons against their gradient, with the pore glutamate E211 serving as the proton-transfer residue.

    Evidence Extracellular pH measurements near cell surface in heterologous expression; E211A mutagenesis

    PMID:16034421

    Open questions at the time
    • Stoichiometry not quantified
    • How antiport (rather than channel) function serves endosomal physiology not yet clear
  7. 2006 High

    CBS-domain crystallography revealed a specific ATP/ADP binding site that directly regulates ClC-5 transport, while in vivo studies linked ClC-5 loss to both renal crystal retention via annexin A2 redistribution and disordered vitamin D metabolism, broadening the phenotypic consequences beyond proteinuria.

    Evidence X-ray crystallography of CBS domain with nucleotides plus oocyte electrophysiology; ClC-5 KO mice with crystal binding and vitamin D pathway measurements; antisense in mIMCD-3 cells

    PMID:16429322 PMID:16672909 PMID:17195847

    Open questions at the time
    • How nucleotide binding allosterically alters transport cycle unknown
    • Whether crystal retention contributes to nephrolithiasis in Dent patients unconfirmed
  8. 2009 High

    Quantification of the 2Cl⁻:1H⁺ antiport stoichiometry, identification of intracellular proton activation (pK ~7.2), discovery of the KIF3B motor interaction, and classification of Dent mutations into trafficking-defective vs. transport-defective classes together built a comprehensive mechanistic framework.

    Evidence Extracellular proton imaging in oocytes; S168P mutagenesis; yeast two-hybrid and endogenous co-IP for KIF3B with live imaging; surface expression and glycosylation analysis of disease mutants

    PMID:19131966 PMID:19657328 PMID:19940036

    Open questions at the time
    • Whether KIF3B interaction is essential for endosomal delivery in vivo untested
    • Structural basis of the 2:1 stoichiometry not resolved
  9. 2010 High

    PY-motif-dependent ubiquitylation by Nedd4-2/WWP2 was shown to be dispensable for ClC-5's endocytic function in vivo, and ClC-5 was uniquely required among CLC family members for proximal tubular endocytosis, eliminating redundancy models.

    Evidence Genetic knock-in mice (PY-motif mutation) compared with KO and ClC-3/ClC-4 double-KO mice; receptor-mediated and fluid-phase endocytosis assays

    PMID:20351103

    Open questions at the time
    • Which internalization/recycling signals besides PY-motif regulate ClC-5 surface expression
    • Why ClC-3 and ClC-4 cannot compensate despite shared localization
  10. 2012 High

    Identification of the ClC-5–megalin–NHERF2 ternary complex and elucidation of the E211 gating glutamate as the major charge-carrying residue in transient capacitive currents established that ClC-5 physically scaffolds the endocytic receptor and that its gating involves intrinsic charge movement prior to Cl⁻ binding.

    Evidence Reciprocal co-IP from rat kidney, NHERF2 siRNA, ternary complex reconstitution; voltage clamp of E211D and E268A mutants in oocytes

    PMID:22349218 PMID:22824269

    Open questions at the time
    • Whether NHERF2 disruption in vivo recapitulates Dent phenotype untested
    • Full gating model lacking structural data on transmembrane conformational changes
  11. 2018 High

    The E211G mutation, which converts ClC-5 from antiporter to pure Cl⁻ channel while preserving normal trafficking and endosomal acidification, demonstrated that coupled H⁺ transport is required for endocytosis through a mechanism beyond simple pH regulation — a key conceptual advance separating the ion-coupling mode from acidification per se.

    Evidence Mutagenesis with electrophysiology in oocytes; endosomal pH measurement with pHluorin2 in HEK293T cells

    PMID:29791050

    Open questions at the time
    • What downstream process requires the antiport mode specifically (e.g. Cl⁻ accumulation, endosomal voltage) remains unidentified
    • Whether this applies in proximal tubule cells in vivo not tested
  12. 2019 High

    Ion-selective microelectrode measurements confirmed the 2:1 Cl⁻:H⁺ stoichiometry and revealed that ClC-5 operates in burst mode, while disease mutant S244L showed altered stoichiometry (1.6:1), directly linking stoichiometric fidelity to disease pathogenesis.

    Evidence Ion-selective microelectrodes in Xenopus oocytes; organelle fluorescent probes; multiple Dent mutant characterization

    PMID:31852738

    Open questions at the time
    • How altered stoichiometry causes endocytic failure mechanistically unclear
    • No high-resolution structure of full-length mammalian ClC-5 available

Open questions

Synthesis pass · forward-looking unresolved questions
  • The key unresolved question is why the antiport coupling mode — rather than simple Cl⁻ conductance — is essential for endocytosis, and whether this reflects a requirement for endosomal Cl⁻ accumulation, specific membrane voltage, or signaling to the megalin–cubilin trafficking machinery.
  • No high-resolution structure of full-length ClC-5 in a lipid membrane
  • The specific downstream effector of antiport-mode coupling in endocytosis is unidentified
  • Whether ClC-5's scaffolding interactions (cofilin, KIF3B, NHERF2-megalin) are independently essential or cooperative in vivo is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6
Localization
GO:0005768 endosome 4 GO:0005886 plasma membrane 4
Pathway
R-HSA-5653656 Vesicle-mediated transport 6 R-HSA-1643685 Disease 5 R-HSA-382551 Transport of small molecules 3
Partners
ANXA2CFL1KIF3BLRP2NHERF2
Complex memberships
ClC-5–megalin–NHERF2 ternary complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 ClC-5 is a Cl⁻/H⁺ antiporter (secondary active transporter), not a classical Cl⁻ channel. It carries protons across the plasma membrane when activated by positive voltages, and can extrude protons against their electrochemical gradient. The pore glutamate E211A mutation abolishes H⁺ transport but not Cl⁻ transport, demonstrating that this residue is critical for proton coupling. Extracellular pH measurements near cell surface in heterologous expression system; site-directed mutagenesis of pore glutamate (E211A) Nature High 16034421
1995 Rat CLC-5 expressed in Xenopus oocytes elicits strongly outwardly rectifying anion currents with conductivity sequence NO₃⁻ > Cl⁻ > Br⁻ > I⁻ >> glutamate⁻, establishing it as a functional ion channel/transporter. Expression is predominantly in kidney. Heterologous expression in Xenopus oocytes; electrophysiology The Journal of biological chemistry High 8537381
1999 ClC-4 and ClC-5 directly mediate plasma membrane currents. Point mutations in ClC-5 alter kinetics, ion selectivity (S168T changes selectivity; E211A changes voltage dependence and ion selectivity), confirming these proteins are the channel-forming subunits. Heterologous expression in Xenopus oocytes and HEK293 cells; site-directed mutagenesis; two-electrode voltage clamp The Journal of biological chemistry High 9873029
2009 ClC-5 operates with a 2 Cl⁻/1 H⁺ antiport stoichiometry. Nitrate uncouples proton transport. Mutation S168P converts ClC-5 into a coupled NO₃⁻/H⁺ exchanger, identifying serine 168 as a determinant of anion specificity. ClC-5 is allosterically stimulated by intracellular protons with apparent pK ~7.2. Novel extracellular proton imaging method in Xenopus oocytes; site-directed mutagenesis at position 168 The EMBO journal High 19131966
2006 The cytoplasmic CBS domain of ClC-5 binds ATP and ADP at a specific nucleotide-binding site with high-micromolar affinity. Point mutations that interfere with nucleotide binding alter the transport behavior of ClC-5 expressed in Xenopus oocytes, demonstrating that CBS-domain nucleotide binding regulates transporter activity. X-ray crystallography of CBS domain with ATP/ADP; equilibrium dialysis; electrophysiology of CBS-domain mutants in Xenopus oocytes Nature structural & molecular biology High 17195847
1999 CLC-5 subcellular distribution in human kidney co-fractionates best with Rab4, a marker of recycling early endosomes, and co-localizes with albumin-containing endocytic vesicles of the receptor-mediated endocytic pathway in proximal tubular cells. Subcellular fractionation of human kidney; immunoblotting with Rab4 marker; confocal microscopy in opossum kidney cells Human molecular genetics High 9931332
2000 CLC-5 knockout mice develop low molecular weight proteinuria, aminoaciduria, glycosuria, hypercalciuria, and severely impaired proximal tubular endocytosis of horseradish peroxidase, demonstrating that CLC-5 is required for endosomal uptake of low molecular weight proteins in vivo. Targeted gene disruption in mice (knockout); horseradish peroxidase endocytosis assay; urinary protein and amino acid analysis Human molecular genetics High 11115837
2003 Loss of ClC-5 in knockout mice impairs endocytosis by causing a trafficking defect of the multiligand receptors megalin and cubilin in proximal tubule cells; megalin and cubilin are selectively lost from the brush border while total kidney content is reduced, despite preserved mRNA levels and normal Rab5a/Rab7 content. ClC-5 KO mouse; 125I-β2-microglobulin uptake assay; Percoll gradient fractionation; quantitative ultrastructural immunogold labeling; immunohistochemistry Proceedings of the National Academy of Sciences of the United States of America High 12815097
2002 Endosomes from ClC-5 knockout mice acidify at a significantly lower rate than wild-type endosomes, consistent with ClC-5 providing an electrical shunt for the H⁺-ATPase. This endosomal acidification defect leads to impaired endocytosis. Additionally, defective PTH endocytosis raises luminal PTH, stimulating apical PTH receptors and causing phosphaturia and secondary up-regulation of proximal tubular α-hydroxylase. Endosomal acidification assay in KO vs. wild-type mice; PTH receptor stimulation studies; vitamin D metabolism measurements Pflugers Archiv : European journal of physiology High 12548389
2003 The C-terminal tail of ClC-5 interacts with cofilin, an actin depolymerizing protein. Phosphorylation of cofilin by LIM kinase 1 stabilizes the actin cytoskeleton and strongly inhibits albumin uptake in proximal tubule cells, linking ClC-5's C-terminus to actin dynamics and receptor-mediated endocytosis. Yeast two-hybrid screen; GST-fusion pulldown; confocal co-localization; LIM kinase 1 overexpression with albumin endocytosis assay The Journal of biological chemistry Medium 12904289
2009 CLC-5 interacts with kinesin family member KIF3B (a microtubule motor) via the COOH-terminus of CLC-5 and the coiled-coil/globular domains of KIF3B. KIF3B overexpression increases CLC-5 surface expression and endocytosis; KIF3B siRNA knockdown has reciprocal effects. CLC-5-containing vesicles transport along KIF3B microtubules. Yeast two-hybrid; GST pulldown; co-immunoprecipitation (including endogenous); confocal live-cell imaging; siRNA knockdown; albumin/transferrin endocytosis assay American journal of physiology. Renal physiology High 19940036
2003 Naturally occurring ClC-5 mutations that truncate the second CBS domain result in failure of ClC-5 to traffic to acidic endosomes; instead, the protein is retained in perinuclear compartments co-localizing with the Golgi complex, identifying CBS domain 2 as required for normal endosomal trafficking. Subcellular localization of CBS domain mutants by confocal microscopy with organelle markers in transfected cells Biochemical and biophysical research communications Medium 14521953
2003 ClC-5 mutations in Dent's disease patients cause altered polarity of H⁺-ATPase in proximal tubule cells (basolateral instead of apical distribution) and loss of apical H⁺-ATPase in α-type intercalated cells, without ultrastructural abnormalities in the endocytic apparatus. Immunohistochemistry of renal biopsies from eight Dent's disease patients with confirmed ClC-5 mutations Kidney international Medium 12631345
2001 CLC-5 in rat intestinal cells co-fractionates with the vacuolar H⁺-ATPase and the early endosomal GTPases Rab4 and Rab5a, localizing it to early endosomes in enterocytes, and partially co-localizes with the transcytosed polymeric immunoglobulin receptor. Western blotting; indirect immunofluorescence; subcellular fractionation with vesicle markers American journal of physiology. Cell physiology Medium 11208533
2005 ClC-5 knockout mice develop a euthyroid goiter with iodine accumulation and decreased pendrin (I⁻/Cl⁻ exchanger) expression (−60% at mRNA and protein levels). ClC-5 localizes to the apical pole of thyrocytes and best co-distributes with late endosomal marker Rab7. Loss of ClC-5 delays apical iodide efflux via pendrin downregulation rather than blocking apical endocytosis of thyroglobulin. ClC-5 KO mouse; thyroid 125I uptake assay; Percoll gradient fractionation; immunolocalization; RT-PCR and Western blot for pendrin Endocrinology Medium 16306076
2010 PY-motif-dependent ubiquitylation of ClC-5 (via WWP2/Nedd4-2 interaction) is dispensable for its role in proximal tubular endocytosis in vivo. Knock-in mice with destroyed PY-motif show no proteinuria or endocytic defects, unlike ClC-5 knockout mice. ClC-5 is unique among CLC proteins in being essential for proximal tubular endocytosis. Genetic knock-in mice (PY-motif point mutation); comparison with KO and double-KO mice lacking ClC-3 or ClC-4; receptor-mediated and fluid-phase endocytosis assays The Journal of biological chemistry High 20351103
2012 ClC-5 and megalin interact directly via their C-termini, and this interaction is scaffolded by NHERF2 in proximal tubule cells. NHERF2 silencing disrupts the ClC-5–megalin complex. A ternary complex of ClC-5, megalin, and NHERF2 was reconstituted with fusion proteins. GST pulldown; reciprocal co-immunoprecipitation from rat kidney lysate; siRNA against NHERF2; reconstitution of ternary complex with fusion proteins The international journal of biochemistry & cell biology Medium 22349218
2012 The gating glutamate Glu211 (external gate) is a major component of the gating charge underlying transient capacitive currents of ClC-5. Mutation E211D shifts transient currents ~150 mV to negative voltages. The gating mechanism involves intrinsic charge movement followed by voltage-dependent low-affinity binding of extracellular Cl⁻ ions. Two-electrode voltage clamp of transport-deficient E268A and E211D ClC-5 mutants in Xenopus oocytes; external and internal Cl⁻ and pH dependence analysis Biophysical journal High 22824269
2013 The strong outward rectification of ClC-5 currents is partly caused by a gating mechanism (not solely transport mechanism), identified through mutation D76H which reveals inward tail currents with 2:1 Cl⁻:H⁺ stoichiometry at negative potentials, allowing reversal potential estimation for the first time. Site-directed mutagenesis (D76H); two-electrode voltage clamp in Xenopus oocytes; external/internal pH and Cl⁻ concentration dependence The Journal of physiology High 24099800
2005 Several Dent's disease CLCN5 missense mutations fail to reach the plasma membrane and are retained in the ER/Golgi, indicating that correct channel structure is required for both function and Golgi exit. The R648X truncation mutant shows increased surface expression due to deletion of a C-terminal PY-like internalization signal. Heterologous expression in Xenopus oocytes and surface ELISA; two-electrode voltage-clamp analysis Human genetics Medium 15895257
2009 Dent's disease CLCN5 mutations fall into distinct mechanistic classes: Type I mutations allow normal trafficking to cell surface and early endosomes but reduce ion currents; Type II mutations cause retention in the ER due to impaired N-glycosylation and protein misfolding. Heterologous expression in Xenopus oocytes and HEK293 cells; N-glycosylation analysis; surface expression assays; confocal localization with endosomal markers Kidney international Medium 19657328
2018 A pathogenic gating-glutamate mutation (E211G) converts ClC-5 from a Cl⁻/H⁺ antiporter into a Cl⁻ channel (abolishes outward rectification and H⁺ sensitivity) while maintaining normal plasma membrane and early endosome localization and normal endosomal acidification, demonstrating that impaired endosomal acidification is not the sole parameter leading to defective endocytosis in Dent disease. Site-directed mutagenesis; two-electrode voltage clamp in Xenopus oocytes; HEK293T expression; endosomal pH measurement with pHluorin2 probe Human mutation High 29791050
2019 ClC-5 exchanges 2 Cl⁻ out for 1 H⁺ in (2:1 stoichiometry confirmed by ion-selective microelectrodes). ClC-5 transport provides net negative charge acting as an 'on-off burst' shunting H⁺-ATPase during endosomal acidification. The S244L Dent mutation has slower transport and altered 1.6:1 stoichiometry; R345W traffics primarily to early endosomes in reduced quantity; Q629* is retained in ER/cis-Golgi. Ion-selective microelectrodes in Xenopus oocytes; organelle-specific fluorescent probes; chemiluminescent surface expression assay The Journal of biological chemistry High 31852738
2006 Disruption of clc-5 in collecting duct cells causes redistribution of annexin A2 from intracellular compartments to the plasma membrane, leading to increased cell-surface crystal retention and agglomeration of calcium phosphate and calcium oxalate crystals, which can be attenuated by anti-annexin A2 antibodies. Antisense clc-5 or truncated clc-5 overexpression in mIMCD-3 cells; immunofluorescence; crystal binding assay with antibody inhibition Cellular and molecular life sciences : CMLS Medium 16429322
2006 In ClC-5 KO mice, kidney-specific upregulation of 1,25(OH)₂-vitamin D₃ target genes occurs despite reduced serum 1,25(OH)₂-vitamin D₃, because impaired proximal tubular endocytosis of the vitamin D precursor leads to increased 1,25(OH)₂-vitamin D₃ in distal nephron segments, contributing to pathogenesis of Dent's disease. Expression profiling, qRT-PCR, and hormone measurements in ClC-5 KO vs. wild-type mice; tissue-specific analysis (kidney, intestine, bone) Kidney international Medium 16672909
2018 CLCN5 is expressed in human podocytes, and its knockdown impairs transferrin endocytosis, decreases cell proliferation, and increases cell migration. A Dent disease mutation (L521F) shows differential subcellular localization compared with wild-type ClC-5 in podocytes, implicating ClC-5 in podocyte protein trafficking and slit diaphragm integrity. CLCN5 knockdown in cultured human podocytes; transferrin endocytosis assay; cell migration/proliferation assays; transfection of L521F mutant with fluorescence localization Kidney international reports Medium 30426109

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 376 16034421
1994 Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM : monthly journal of the Association of Physicians 257 7922301
2003 Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proceedings of the National Academy of Sciences of the United States of America 254 12815097
2000 Mice lacking renal chloride channel, CLC-5, are a model for Dent's disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Human molecular genetics 247 11115837
1999 Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Human molecular genetics 239 9931332
1995 Cloning and functional expression of rat CLC-5, a chloride channel related to kidney disease. The Journal of biological chemistry 238 8537381
1999 Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents. The Journal of biological chemistry 208 9873029
2010 Dent's disease. Orphanet journal of rare diseases 167 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 134 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 134 7874126
2006 Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5. Nature structural & molecular biology 128 17195847
1995 Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics 124 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 Tubular proteinuria defined by a study of Dent's (CLCN5 mutation) and other tubular diseases. Kidney international 86 10620205
1993 Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. Human molecular genetics 84 8111383
2009 Conversion of the 2 Cl(-)/1 H+ antiporter ClC-5 in a NO3(-)/H+ antiporter by a single point mutation. The EMBO journal 82 19131966
2010 Dent's disease: clinical features and molecular basis. Pediatric nephrology (Berlin, Germany) 78 20936522
2000 Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis. Kidney international 78 10720930
2003 Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines. The Journal of biological chemistry 77 12904289
2015 Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1. Human mutation 74 25907713
2003 Altered polarity and expression of H+-ATPase without ultrastructural changes in kidneys of Dent's disease patients. Kidney international 67 12631345
2001 Tissue distribution and subcellular localization of the ClC-5 chloride channel in rat intestinal cells. American journal of physiology. Cell physiology 66 11208533
1998 Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease. Kidney international 66 9853249
2005 The loss of the chloride channel, ClC-5, delays apical iodide efflux and induces a euthyroid goiter in the mouse thyroid gland. Endocrinology 65 16306076
1998 The swelling-activated chloride channel ClC-2, the chloride channel ClC-3, and ClC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells. The Journal of clinical investigation 65 9449697
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
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
2003 A role for CBS domain 2 in trafficking of chloride channel CLC-5. Biochemical and biophysical research communications 50 14521953
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
2015 IL-4 Up-Regulates MiR-21 and the MiRNAs Hosted in the CLCN5 Gene in Chronic Lymphocytic Leukemia. PloS one 46 25909590
2000 Characterization of renal chloride channel (CLCN5) mutations in Dent's disease. Journal of the American Society of Nephrology : JASN 46 10906159
2011 ClC-5 mutations associated with Dent's disease: a major role of the dimer interface. Pflugers Archiv : European journal of physiology 45 22083641
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
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
2009 Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney international 38 19657328
2010 A novel CLCN5 mutation in a boy with Bartter-like syndrome and partial growth hormone deficiency. Pediatric nephrology (Berlin, Germany) 34 20680351
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
1998 CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. Kidney international 33 9452997
2020 From protein uptake to Dent disease: An overview of the CLCN5 gene. Gene 32 32289351
2005 Characterization of a novel vpu-harboring simian immunodeficiency virus from a Dent's Mona monkey (Cercopithecus mona denti). Journal of virology 32 15956597
2015 Nephrolithiasis, kidney failure and bone disorders in Dent disease patients with and without CLCN5 mutations. SpringerPlus 31 26389017
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
2006 Disruption of clc-5 leads to a redistribution of annexin A2 and promotes calcium crystal agglomeration in collecting duct epithelial cells. Cellular and molecular life sciences : CMLS 30 16429322
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
2012 On the mechanism of gating charge movement of ClC-5, a human Cl(-)/H(+) antiporter. Biophysical journal 29 22824269
2005 The Alu insertion in the CLCN5 gene of a patient with Dent's disease leads to exon 11 skipping. Journal of human genetics 29 16041495
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
2006 Kidney-specific upregulation of vitamin D3 target genes in ClC-5 KO mice. Kidney international 25 16672909
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
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 24 22349218
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
2010 Role of CFTR and ClC-5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 22 21063094
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
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
2004 Comparative ontogeny, processing, and segmental distribution of the renal chloride channel, ClC-5. Kidney international 21 14675051
2017 ClC5 Decreases the Sensitivity of Multiple Myeloma Cells to Bortezomib via Promoting Prosurvival Autophagy. Oncology research 20 28899456
2013 A single point mutation reveals gating of the human ClC-5 Cl-/H+ antiporter. The Journal of physiology 20 24099800
2007 Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic machinery in Dent's disease. Nephron. Physiology 20 18025833
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 20 13679301
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
2023 The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype. Kidney international reports 18 37284679
2015 Chloride-hydrogen antiporters ClC-3 and ClC-5 drive osteoblast mineralization and regulate fine-structure bone patterning in vitro. Physiological reports 18 26603451
2020 Genetic Analyses in Dent Disease and Characterization of CLCN5 Mutations in Kidney Biopsies. International journal of molecular sciences 17 31947599
2001 The voltage-dependent Cl(-) channel ClC-5 and plasma membrane Cl(-) conductances of mouse renal collecting duct cells (mIMCD-3). The Journal of physiology 17 11691871
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
2009 ClC-5 regulates dentin development through TGF-beta1 pathway. Archives of oral biology 16 19878925
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
2019 Prevalence of low molecular weight proteinuria and Dent disease 1 CLCN5 mutations in proteinuric cohorts. Pediatric nephrology (Berlin, Germany) 15 30852663
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 15 31852738
2016 Functional and transport analyses of CLCN5 genetic changes identified in Dent disease patients. Physiological reports 15 27117801
2015 A tale of two CLCs: biophysical insights toward understanding ClC-5 and ClC-7 function in endosomes and lysosomes. The Journal of physiology 15 26036722
2012 Vitamin A deficiency associated with urinary retinol binding protein wasting in Dent's disease. Pediatric nephrology (Berlin, Germany) 15 22350370
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 15 17262170
2004 Calcium phosphate and calcium oxalate crystal handling is dependent upon CLC-5 expression in mouse collecting duct cells. Biochimica et biophysica acta 15 15158917
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 15 12886045
2000 Isolation and characterization of the human CLC-5 chloride channel gene promoter. Gene 15 11167024