Affinage

CLCN7

H(+)/Cl(-) exchange transporter 7 · UniProt P51798

Length
805 aa
Mass
88.7 kDa
Annotated
2026-06-09
98 papers in source corpus 24 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLCN7 (CLC-7) is a lysosomal 2Cl-/1H+ antiporter that provides the predominant chloride permeability of the lysosomal membrane and is essential for lysosomal ion homeostasis, acidification, and protein degradation (PMID:18449189, PMID:19661288). It functions in obligate complex with the β-subunit OSTM1: the two proteins co-localize in late endosomes/lysosomes, OSTM1 stabilizes CLC-7 protein, and CLC-7 in turn delivers OSTM1 to lysosomes (PMID:16525474); cryo-EM structures show a glycosylated, disulfide-bonded OSTM1 dimer forming a lid that covers the luminal surface of CLC-7 and shields it from luminal degradation while interacting extensively within the membrane (PMID:32749217, PMID:32851177). Transport is governed by a slow common gate that acts on both protomers of the dimer simultaneously and depends on the CBS-domain-containing cytosolic C-terminus (PMID:23983121), which is tonically inhibited by the signaling lipid PI(3,5)P2 through a conformational remodeling that draws the cytosolic and transmembrane domains together (PMID:35670560). Beyond its catalytic activity, CLC-7 protein has transport-independent roles: in vivo structure-function dissection separates ion transport (critical for osteopetrosis and lysosomal storage) from protein-protein interactions that mediate pigmentation (PMID:24820037). CLC-7 is required cell-autonomously for lysosomal protein degradation and its loss produces lysosomal storage and neurodegeneration (PMID:15706348, PMID:19661288), for microglial phagocytic clearance of apoptotic cells and amyloid-β (PMID:38294065), and for osteoclast ruffled-border function, with its transcription directly co-regulated with OSTM1 by the MITF transcription factor during osteoclastogenesis (PMID:17105730). Gain-of-function CLCN7 mutations that lose PI(3,5)P2 inhibition cause HOD syndrome and giant lysosomal vacuoles through excessive Cl-/H+ exchange (PMID:38838776), while trafficking-defective and gating-accelerating mutations cause autosomal dominant osteopetrosis (PMID:20830208, PMID:24159188).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 Medium

    Established CLC-7 as a distinct branch of the CLC chloride transporter family, but its function was unknown because it produced no currents when expressed alone.

    Evidence Molecular cloning, heterologous expression in Xenopus oocytes, chromosomal mapping to 16p13

    PMID:8543009

    Open questions at the time
    • No functional activity detected in isolation
    • Requirement for an accessory subunit not yet recognized
    • Subcellular localization unresolved
  2. 2005 High

    Defined CLC-7 as essential for lysosomal function in vivo, revealing lysosomal storage and cell-autonomous neurodegeneration distinct from gross pH change.

    Evidence Clcn7 knockout mouse with histology, EM, and osteoclast-specific transgenic rescue

    PMID:15706348

    Open questions at the time
    • Molecular transport mechanism not defined
    • Reason for normal neuronal lysosomal pH despite storage unexplained
  3. 2006 High

    Identified OSTM1 as the obligate β-subunit that stabilizes CLC-7 and showed reciprocal trafficking dependence, explaining the earlier null oocyte result.

    Evidence Reciprocal Co-IP, immunofluorescence co-localization, protein quantification in grey-lethal mice

    PMID:16525474

    Open questions at the time
    • Structural basis of stabilization unknown
    • Mechanism of luminal OSTM1 cleavage not resolved
  4. 2006 High

    Connected CLC-7 expression to osteoclast biology by establishing MITF as a direct transcriptional regulator of both Clcn7 and Ostm1.

    Evidence EMSA, ChIP, reporter assays, MITF microarray, and mi/mi mutant mice

    PMID:17105730

    Open questions at the time
    • Co-regulatory inputs beyond MITF not mapped
    • Regulation in non-osteoclast tissues unaddressed
  5. 2008 High

    Directly demonstrated CLC-7 as the predominant lysosomal Cl-/H+ antiporter required for lysosomal acidification.

    Evidence Electrophysiology of isolated lysosomes plus siRNA knockdown with acidification readout

    PMID:18449189

    Open questions at the time
    • Gating regulation not yet characterized
    • Coupling stoichiometry not defined here
  6. 2009 High

    Pinpointed CLC-7 to the degradation step of endocytosed protein, showing the defect is cell-autonomous and not at the endocytosis stage.

    Evidence Tissue-specific Clcn7 knockout with in vivo pulse-chase of endocytosed protein

    PMID:19661288

    Open questions at the time
    • Link between Cl- transport and proteolytic enzyme activity not yet mechanistically defined
  7. 2013 High

    Resolved the gating architecture, showing slow activation is a common gate on the dimer requiring the CBS-containing C-terminus, which need not be covalently attached.

    Evidence Electrophysiology of plasma-membrane-targeted CLC-7/Ostm1 with mutant co-expression and domain swaps

    PMID:23983121

    Open questions at the time
    • Physiological signal controlling the gate not yet identified
    • Structural conformations of gating states unresolved
  8. 2020 High

    Provided the structural basis of the complex, showing the OSTM1 dimer as a protective luminal lid and identifying domain interfaces that tune slow gating.

    Evidence Cryo-EM of CLC-7 and CLC-7/OSTM1 with accompanying electrophysiology

    PMID:32749217 PMID:32851177

    Open questions at the time
    • Conformational dynamics during gating not captured by static structures
    • Regulatory ligand binding sites not yet localized
  9. 2014 High

    Separated transport-dependent from transport-independent functions of CLC-7 using engineered knock-in mice, showing pigmentation depends on protein interaction while osteopetrosis depends on ion transport.

    Evidence Clcn7unc/unc and Clcn7td/td knock-in mice compared to knockout, multiple phenotypic readouts

    PMID:24820037

    Open questions at the time
    • Identity of transport-independent interaction partners for pigmentation not established
  10. 2022 High

    Identified PI(3,5)P2 as a direct tonic inhibitor of CLC-7 transport and linked loss of this regulation to gain-of-function disease.

    Evidence PIKfyve inhibition, direct transport assay, gain-of-function mutant, lysosomal pH measurement

    PMID:35670560

    Open questions at the time
    • Structural mechanism of lipid inhibition not yet resolved at this stage
  11. 2025 High

    Established the structural mechanism of PI(3,5)P2 regulation, showing lipid binding remodels the cytosolic-transmembrane interface to control the slow gate.

    Evidence Cryo-EM, functional transport assays, molecular dynamics, and PI(3,5)P2-site mutagenesis (preprint)

    Open questions at the time
    • Preprint not yet peer-reviewed
    • Kinetics of lipid-induced conformational transitions not fully resolved
  12. 2024 High

    Connected CLC-7 gain-of-function to human HOD syndrome, demonstrating reduced PI(3,5)P2 inhibition, shifted gating, and Cl-/H+-exchange-dependent vacuole formation.

    Evidence Electrophysiology, uncoupling mutagenesis, PI(3,5)P2 binding analysis, patient fibroblast imaging

    PMID:38838776

    Open questions at the time
    • Tissue-specific basis of hypopigmentation, organomegaly, and delayed myelination not dissected
  13. 2025 Medium

    Placed CLC-7 in a trafficking and lysosome-distribution network in osteoclasts via physical interaction with SNX10 and control of peripheral OSTM1-lysosome positioning.

    Evidence Co-IP, co-localization, and comparison of CLC-7-KO, SNX10-KO, and OSTM1-KO osteoclast phenotypes

    PMID:41408708

    Open questions at the time
    • Direct SNX10–CLC-7 interface unmapped
    • Whether SNX10 regulates CLC-7 transport activity unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLC-7/OSTM1 gating signals, lipid regulation, and trafficking inputs are integrated to set lysosomal Cl- and pH across different cell types remains unresolved.
  • Physiological trigger of slow gating in vivo not identified
  • Cell-type-specific trafficking determinants incompletely defined
  • Quantitative model linking Cl- transport to cathepsin/proteolytic output lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 1
Localization
GO:0005764 lysosome 4 GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-9612973 Autophagy 2 R-HSA-1266738 Developmental Biology 1 R-HSA-382551 Transport of small molecules 1 R-HSA-392499 Metabolism of proteins 1 R-HSA-74160 Gene expression (Transcription) 1
Partners
MITFOSTM1SNX10
Complex memberships
CLC-7/OSTM1 antiporter complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 ClC-7 is a Cl-/H+ antiporter that constitutes the primary (predominant) Cl- permeability of the lysosomal membrane. siRNA knockdown of ClC-7 essentially ablates lysosomal Cl-/H+ antiport activity and strongly diminishes the ability of lysosomes to acidify in vivo, demonstrating ClC-7's essential role in lysosomal acidification. Direct electrophysiological measurement of anion transport in isolated lysosomes; siRNA knockdown with functional readout of Cl-/H+ antiport activity and lysosomal acidification Nature High 18449189
2006 ClC-7 requires Ostm1 as an obligate β-subunit. The two proteins co-localize in late endosomes/lysosomes and the ruffled border of osteoclasts, form a molecular complex by co-immunoprecipitation, and Ostm1 stabilizes ClC-7 protein (ClC-7 protein levels fall below 10% in Ostm1-deficient tissues). ClC-7 is required for Ostm1 to reach lysosomes, where the highly glycosylated Ostm1 luminal domain is then cleaved. Co-immunoprecipitation, co-localization by immunofluorescence, protein-level analysis in grey-lethal (Ostm1-deficient) mice, subcellular fractionation Nature High 16525474
2020 Cryo-EM structures of CLC-7 alone and in complex with OSTM1 resolved to 2.8 Å reveal that the luminal surface of CLC-7 is entirely covered by a dimer of heavily glycosylated, disulfide-bonded OSTM1, which protects CLC-7 from the degradative lysosomal lumen. OSTM1 binding does not induce large-scale rearrangements of CLC-7 but has minor effects on the ion-conduction pathway conformation. Cryo-electron microscopy structure determination eLife High 32749217 32851177
2020 Cryo-EM structure of human CLC-7/Ostm1 shows that the glycosylated Ostm1 acts as a lid positioned above CLC-7 and interacts extensively with CLC-7 within the membrane. Structural and electrophysiology analyses indicate that domain interaction interfaces between the N-terminus, transmembrane domain (TMD), and CBS domains of CLC-7 affect its slow gating kinetics. Cryo-EM structure determination; electrophysiology Science advances High 32851177
2005 ClC-7 knockout mice develop lysosomal storage disease and neurodegeneration (accumulation of electron-dense material, autofluorescent structures, subunit c of mitochondrial ATP synthase, microglial activation, astrogliosis) despite unchanged lysosomal pH in cultured neurons, demonstrating a role for ClC-7 in lysosomal function independent of gross pH change in neurons. Rescuing the bone phenotype by osteoclast-specific transgenic expression revealed progressive CNS pathology, showing cell-autonomous neurodegeneration. Clcn7 knockout mouse model; histology; electron microscopy; transgenic rescue; immunohistochemistry The EMBO journal High 15706348
2009 ClC-7 is required for lysosomal protein degradation in a cell-autonomous manner. In renal proximal tubular cells lacking ClC-7 (tissue-specific knockout), endocytosed protein half-life increased significantly compared to ClC-7-expressing cells, while endocytosis rates were similar, demonstrating that ClC-7 is specifically required for the degradation step. Tissue-specific Clcn7 knockout mice; in vivo pulse-chase endocytosis experiments; comparison of endocytosed protein half-life between ClC-7-expressing and ClC-7-deficient cells FASEB journal High 19661288
2013 Slow voltage-dependent activation of ClC-7/Ostm1 operates through a common gate acting on both subunits of the dimer simultaneously (not through independent protopore gates). CBS domain-containing C-terminus is required for this common gating and does not need to be covalently attached to the membrane domain of ClC-7. Electrophysiology of plasma-membrane-targeted ClC-7/Ostm1; co-expression of transport-deficient and accelerating mutant subunits; truncation and domain swap experiments The Journal of biological chemistry High 23983121
2022 PI(3,5)P2 directly inhibits ClC-7 Cl-/H+ transport. Depletion of PI(3,5)P2 by PIKfyve kinase inhibition causes lysosomal hyperacidification primarily via an effect on ClC-7. A disease-causing gain-of-function ClC-7 mutation eliminates PI(3,5)P2 inhibition, linking this regulatory mechanism to disease pathogenesis. PIKfyve inhibition; direct transport assay of ClC-7; gain-of-function mutant analysis; lysosomal pH measurements eLife High 35670560
2025 PI(3,5)P2 binding to ClC-7 dramatically remodels ClC-7 structure by inducing close association between cytosolic and transmembrane domains. Disease-causing gain-of-function mutations show increased transport activity through loss of PI(3,5)P2 binding. ClC-7 activation correlates with dissociation and increased disorder of the cytoplasmic domain and novel transmembrane domain conformations, revealing the molecular basis of the ClC-7 slow gate regulation by PI(3,5)P2. Cryo-EM structural analysis; functional transport assays; computational/molecular dynamics analysis; mutagenesis of PI(3,5)P2-binding site bioRxivpreprint High
2014 Both ClC-7 ion transport activity and ClC-7 protein presence (independent of ion transport) are required for different cellular functions. Converting ClC-7 into a Cl- conductance (Clcn7unc/unc) causes lysosomal storage but less severe osteopetrosis; transport-deficient ClC-7 (Clcn7td/td) causes severe osteopetrosis comparable to knockout, but normal coat color and less severe neurodegeneration, indicating that protein-protein interactions (not ion transport) mediate pigmentation, while ion transport is critical for osteopetrosis and lysosomal function. In vivo structure-function analysis using Clcn7unc/unc (conductance-converted) and Clcn7td/td (transport-deficient) knock-in mice; phenotypic comparison with Clcn7-/- mice EMBO reports High 24820037
2006 Microphthalmia transcription factor (MITF) directly binds to two M-box elements in the Clcn7 promoter and one M-box in the Ostm1 promoter, co-regulating their expression during osteoclastogenesis. MITF transactivates the Clcn7 promoter, and mutation of one M-box abolishes this transactivation. Clcn7 expression is repressed in mi/mi dominant-negative MITF mice. EMSA; reporter gene assay; chromatin immunoprecipitation; MITF overexpression microarray; analysis of mi/mi mutant mice The Journal of biological chemistry High 17105730
2011 In primary microglia, ClC-7 is not efficiently delivered to lysosomes (it is mistargeted and degraded by ER-associated degradation), causing incomplete lysosomal acidification and impaired degradation of fibrillar amyloid-β. Macrophage colony-stimulating factor (M-CSF) activation induces trafficking of ClC-7 to lysosomes, restoring acidification and fAβ degradation. ClC-7 association with Ostm1 is important for correct lysosomal targeting in microglia. Primary microglia culture; ClC-7 localization by immunofluorescence; lysosomal pH measurement; fAβ degradation assay; M-CSF activation; Ostm1 co-expression Molecular biology of the cell Medium 21441306
2010 The G215R mutation in ClC-7 (causing autosomal dominant osteopetrosis type II) does not abolish Cl-/H+ antiport function but causes a severe trafficking defect, preventing the transporter from reaching the lysosomal membrane in CHO cells. This suggests mislocalization rather than loss of catalytic activity is the primary pathogenic mechanism for G215R. Solid-supported membrane-based electrophysiology; subcellular localization in CHO cells expressing wild-type vs. G213R rat ClC-7 PloS one Medium 20830208
2013 A Y750Q missense mutation in the CBS2 domain of ClC-7 in Belgian Blue cattle drastically accelerates voltage-dependent gating of ClC-7/Ostm1 while largely preserving lysosomal localization and assembly, providing direct evidence that accelerated ClC-7/Ostm1 gating per se (independent of mislocalization) is sufficient to cause osteopetrosis and lysosomal storage disease. Autozygosity mapping; genome sequencing; electrophysiology of mutant ClC-7/Ostm1; immunolocalization; clinical/histological phenotyping Disease models & mechanisms Medium 24159188
2021 Wild-type ClC-7 displays large transient capacitive currents that depend on external pH and internal (but not external) Cl-. The proton glutamate mutant E312A strongly reduces but does not abolish stationary transport currents (unlike in other mammalian CLC transporters), suggesting that an alternative proton transfer pathway exists in ClC-7. Electrophysiology (patch clamp) of plasma membrane-targeted wild-type and E312A mutant ClC-7; analysis of transient capacitive currents and stationary transport currents The Journal of general physiology Medium 33211806
2024 Gain-of-function CLCN7 mutations (p.Tyr715Cys and p.Lys285Thr) causing HOD syndrome (hypopigmentation, organomegaly, delayed myelination) decrease ClC-7 inhibition by PI(3,5)P2, affect residues lining its binding pocket, shift voltage-dependent gating to less positive potentials (an effect partially transferred to WT subunits in heteromers), and induce large lysosomal vacuoles. The vacuole formation requires Cl-/H+ exchange activity as shown by uncoupling mutations. Fibroblasts from p.Y715C patient display giant vacuoles. Electrophysiology; mutagenesis (uncoupling mutations); PI(3,5)P2 binding analysis; patient fibroblast imaging; vacuole formation assay in transfected cells The Journal of biological chemistry High 38838776
2023 ClC-7 gain-of-function mutation (Y715C) causes enlarged lysosomal vacuoles through increased Cl-/H+ exchange activity leading to membrane fusion; degradation of endocytosed material is reduced in these compartments; autophagic clearance is largely impaired resulting in accumulation of autophagic material. The vacuole enlargement requires Cl-/H+ exchange (demonstrated by uncoupling mutations that abrogate it). Transfection of mutant ClC-7 in cells; combination with uncoupling or current-reducing mutations; lysosomal morphology analysis; autophagic flux assay; endocytosis/degradation assays Biomolecules Medium 38136669
2023 ClC-7 transport activity is inhibited by low luminal (extracellular in the assay) Cl- concentration, in contrast to ClC-6 which is activated by high luminal Cl-. This distinctive Cl- sensitivity of ClC-7/Ostm1 is proposed to serve as a feedback mechanism limiting excessive intraluminal Cl- accumulation in lysosomes. An osteopetrosis mutant (R762Q) with fast gating kinetics shows altered (reduced) Cl- sensitivity, identifying altered Cl- sensitivity as a plausible disease mechanism. Electrophysiology of plasma membrane-targeted ClC-7/Ostm1 and ClC-6 with varying extracellular Cl- concentrations; disease mutant analysis The Journal of physiology Medium 37937509
2023 Genetic knockout of CLCN7 corrects lysosomal swelling and partially corrects lysosomal hyperacidification in FIG4-null cells, placing ClC-7 downstream of PI(3,5)P2 signaling in lysosomal homeostasis. Knockout of the related transporter CLCN6 in FIG4-null cells had no effect on the lysosome phenotype, demonstrating specificity of CLCN7 in this pathway. Genetic epistasis: CLCN7 and CLCN6 knockout in FIG4-null cell cultures; lysosomal size and pH measurements; in vivo mouse model with dominant-negative CLCN7 PLoS genetics Medium 37363915
2020 In PSEN1-deficient cells, ClC-7 delivery from the ER to lysosomes is impaired, reducing lysosomal Cl- content. PKA-mediated (β2-adrenergic agonist-stimulated) facilitation of ClC-7 delivery to lysosomes restores lysosomal Cl-, acidification, proteolysis, calcium homeostasis, and autophagic flux. This identifies a β2-adrenergic/PKA → ClC-7 lysosomal trafficking axis as a mechanism for lysosomal pH regulation. β2-adrenergic agonist treatment; PKA pathway analysis; ClC-7 subcellular localization by imaging; lysosomal pH, Cl- content, proteolysis, and autophagic flux assays in PSEN1 KO cells and patient fibroblasts; transcriptomics Journal of molecular biology Medium 32105735
2017 ClC-7 is expressed in the luminal (apical) membrane domain of choroid plexus epithelial cells, where it is proposed to contribute to CSF pH regulation via Cl-/H+ exchange. Cl- gradient-driven changes in intracellular pH and membrane potential consistent with Cl-/H+ exchange were demonstrated by dynamic imaging. Mass spectrometry proteomics of FACS-isolated choroid plexus epithelial cells; RT-PCR; immunolocalization; dynamic intracellular pH and membrane potential imaging American journal of physiology. Cell physiology Low 29351414
2025 SNX10 physically interacts with CLC-7 (demonstrated by co-immunoprecipitation). CLC-7 is required for transport of OSTM1-containing lysosomes to the cell periphery in osteoclasts. Loss of CLC-7 depletes peripheral OSTM1-containing lysosomes, establishing a functional link between SNX10, CLC-7, and OSTM1 in regulating lysosome subcellular distribution and osteoclast fusion/function. Co-immunoprecipitation; immunofluorescence co-localization; analysis of CLC-7-KO osteoclasts for peripheral lysosome distribution; comparison with SNX10-KO and OSTM1-KO phenotypes Journal of bone and mineral research Medium 41408708
2024 ClC-7 is essential for phagocytic clearance by microglia in vivo. In zebrafish clcn7 mutants, microglia and embryonic macrophages cannot effectively process apoptotic cells or β-amyloid. Despite these functional defects, microglia develop normally and express normal endosomal/lysosomal markers. The ostm1 (β-subunit) mutant displays a strikingly similar phenotype, consistent with ClC-7/Ostm1 complex being required for microglial lysosomal function. Zebrafish clcn7 and ostm1 mutant analysis; in vivo phagocytosis assays; microglial development and marker expression analysis Journal of cell science Medium 38294065
2025 CLC-7 depletion (siRNA knockdown or pharmacological inhibition) enhances rAAV transduction efficiency by altering lysosomal chloride homeostasis, selectively reducing the catalytic activity of cathepsins B and L (Cl--dependent) without affecting cathepsin D (Cl--independent), thereby delaying rAAV capsid degradation and facilitating lysosomal escape. siRNA knockdown; pharmacological inhibition of CLC-7; cathepsin activity assays; rAAV transduction efficiency measurement in vitro and in vivo mouse model Journal of medical virology Medium 41674487
1995 ClC-7 (89 kDa) and ClC-6 (97 kDa) define a new branch of the CLC chloride channel family; ClC-7 is located on human chromosome 16p13. ClC-7 is the only known eukaryotic CLC protein lacking the conserved glycosylation site between transmembrane domains D8 and D9. Neither ClC-6 nor ClC-7 expressed functional chloride channels in Xenopus oocytes when expressed alone or in combination. Molecular cloning; heterologous expression in Xenopus oocytes; sequence/hydropathy analysis; chromosomal mapping FEBS letters Medium 8543009

Source papers

Stage 0 corpus · 98 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes. Nature 319 18449189
2005 Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration. The EMBO journal 288 15706348
2001 Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Human molecular genetics 283 11741829
2006 ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 271 16525474
2003 Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 179 14584882
1995 ClC-6 and ClC-7 are two novel broadly expressed members of the CLC chloride channel family. FEBS letters 156 8543009
2004 Characterization of osteoclasts from patients harboring a G215R mutation in ClC-7 causing autosomal dominant osteopetrosis type II. The American journal of pathology 101 15111300
2011 Degradation of Alzheimer's amyloid fibrils by microglia requires delivery of ClC-7 to lysosomes. Molecular biology of the cell 86 21441306
2003 Chloride channel 7 (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 81 12929941
2009 Lysosomal degradation of endocytosed proteins depends on the chloride transport protein ClC-7. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 78 19661288
2002 Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis. Human genetics 66 12522560
2010 Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations. Human mutation 65 19953639
2006 The expression of Clcn7 and Ostm1 in osteoclasts is coregulated by microphthalmia transcription factor. The Journal of biological chemistry 64 17105730
2022 Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance. eLife 62 35670560
2020 Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. eLife 59 32749217
2010 Distinct neuropathologic phenotypes after disrupting the chloride transport proteins ClC-6 or ClC-7/Ostm1. Journal of neuropathology and experimental neurology 53 21107136
2020 Molecular insights into the human CLC-7/Ostm1 transporter. Science advances 50 32851177
2014 Transport activity and presence of ClC-7/Ostm1 complex account for different cellular functions. EMBO reports 50 24820037
2010 The G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. PloS one 42 20830208
2013 Common gating of both CLC transporter subunits underlies voltage-dependent activation of the 2Cl-/1H+ exchanger ClC-7/Ostm1. The Journal of biological chemistry 40 23983121
2014 CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 38 24108692
2013 A missense mutation accelerating the gating of the lysosomal Cl-/H+-exchanger ClC-7/Ostm1 causes osteopetrosis with gingival hamartomas in cattle. Disease models & mechanisms 37 24159188
2021 Efficient generation of osteoclasts from human induced pluripotent stem cells and functional investigations of lethal CLCN7-related osteopetrosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 36 33905594
2002 Activation by acidic pH of CLC-7 expressed in oocytes from Xenopus laevis. Biochemical and biophysical research communications 35 11846422
2015 The ClC-7 Chloride Channel Is Downregulated by Hypoosmotic Stress in Human Chondrocytes. Molecular pharmacology 31 25943117
2010 Severe developmental bone phenotype in ClC-7 deficient mice. Developmental biology 31 20599900
2001 Localization of mouse CLC-6 and CLC-7 mRNA and their functional complementation of yeast CLC gene mutant. Histochemistry and cell biology 31 11326746
2020 β2-adrenergic Agonists Rescue Lysosome Acidification and Function in PSEN1 Deficiency by Reversing Defective ER-to-lysosome Delivery of ClC-7. Journal of molecular biology 30 32105735
2005 The role of chloride channels in osteoclasts: ClC-7 as a target for osteoporosis treatment. Drug news & perspectives 29 16391718
2019 ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth. Theranostics 28 30867839
2004 In vitro differentiation of CD14 cells from osteopetrotic subjects: contrasting phenotypes with TCIRG1, CLCN7, and attachment defects. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 15231021
2005 Polymorphisms of the CLCN7 gene are associated with BMD in women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 27 16234969
2005 Polymorphisms in the CLCN7 gene modulate bone density in postmenopausal women and in patients with autosomal dominant osteopetrosis type II. The Journal of clinical endocrinology and metabolism 26 16368748
2003 Type II benign osteopetrosis (Albers-Schönberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations. Calcified tissue international 26 14564431
2011 Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery 25 21962762
2009 Identification of the CLCN7 gene mutations in two Chinese families with autosomal dominant osteopetrosis (type II). Journal of bone and mineral metabolism 25 19288050
2015 Effective Small Interfering RNA Therapy to Treat CLCN7-dependent Autosomal Dominant Osteopetrosis Type 2. Molecular therapy. Nucleic acids 23 26325626
2015 Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADO-II) and intermediate autosomal recessive osteopetrosis (IARO) in Chinese patients. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 22 26395888
2011 The virulence gene and clinical phenotypes of osteopetrosis in the Chinese population: six novel mutations of the CLCN7 gene in twelve osteopetrosis families. Journal of bone and mineral metabolism 22 21947783
2009 Characteristics of ClC7 Cl- channels and their inhibition in mutant (G215R) associated with autosomal dominant osteopetrosis type II in native osteoclasts and hClcn7 gene-expressing cells. Pflugers Archiv : European journal of physiology 21 19543743
2020 Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Derived From Structural and Functional Analysis of 14 ClC-7 Mutants. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 19 33125761
2008 Characterization of acid flux in osteoclasts from patients harboring a G215R mutation in ClC-7. Biochemical and biophysical research communications 18 19070589
2019 Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis. Molecular medicine reports 16 30942407
2015 Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II). Journal of bone and mineral metabolism 16 26056022
2022 CLCN7, a gene shared by autosomal recessive and autosomal dominant osteopetrosis. Bone 15 36513280
2019 Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications. Bone research 15 31231577
2016 Enhanced but hypofunctional osteoclastogenesis in an autosomal dominant osteopetrosis type II case carrying a c.1856C>T mutation in CLCN7. Bone research 15 27990310
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
1999 Complete genomic structure of the CLCN6 and CLCN7 putative chloride channel genes(1). Biochimica et biophysica acta 15 10500249
2023 The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants. PLoS genetics 14 37363915
2016 ClC-7 Deficiency Impairs Tooth Development and Eruption. Scientific reports 14 26829236
2021 Large transient capacitive currents in wild-type lysosomal Cl-/H+ antiporter ClC-7 and residual transport activity in the proton glutamate mutant E312A. The Journal of general physiology 13 33211806
2018 Generation of a human induced pluripotent stem cell line (BIHi002-A) from a patient with CLCN7-related infantile malignant autosomal recessive osteopetrosis. Stem cell research 13 30763735
2013 A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series. Journal of medical case reports 13 23302420
2011 Antibodies against ClC7 inhibit extracellular acidification-induced Cl⁻ currents and bone resorption activity in mouse osteoclasts. Naunyn-Schmiedeberg's archives of pharmacology 13 21061117
2024 Gain-of-function variants in CLCN7 cause hypopigmentation and lysosomal storage disease. The Journal of biological chemistry 12 38838776
2017 The murine choroid plexus epithelium expresses the 2Cl-/H+ exchanger ClC-7 and Na+/H+ exchanger NHE6 in the luminal membrane domain. American journal of physiology. Cell physiology 12 29351414
2016 Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation. American journal of medical genetics. Part A 12 27540713
2015 A novel mutation and a known mutation in the CLCN7 gene associated with relatively stable infantile malignant osteopetrosis in a Chinese patient. Gene 12 26477479
2016 Novel CLCN7 mutation identified in a Han Chinese family with autosomal dominant osteopetrosis-2. Molecular pain 11 27325559
2012 Long-term survival in infantile malignant autosomal recessive osteopetrosis secondary to homozygous p.Arg526Gln mutation in CLCN7. American journal of medical genetics. Part A 11 22419446
2010 An alternative splicing variant in Clcn7-/- mice prevents osteopetrosis but not neural and retinal degeneration. Veterinary pathology 11 20448277
2009 A novel CLCN7 mutation resulting in a most severe form of autosomal recessive osteopetrosis. European journal of pediatrics 11 19238435
2017 ClC-7/Ostm1 contribute to the ability of tea polyphenols to maintain bone homeostasis in C57BL/6 mice, protecting against fluorosis. International journal of molecular medicine 10 28339032
2023 Impaired Autophagic Clearance with a Gain-of-Function Variant of the Lysosomal Cl-/H+ Exchanger ClC-7. Biomolecules 9 38136669
2014 Identification of TCIRG1 and CLCN7 gene mutations in a patient with autosomal recessive osteopetrosis. Molecular medicine reports 9 24535484
2013 An optical assay of the transport activity of ClC-7. Scientific reports 9 23390581
2020 Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive osteopetrosis. Molecular genetics & genomic medicine 8 32691986
2017 Clcn7F318L/+ as a new mouse model of Albers-Schönberg disease. Bone 8 28942122
2017 Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis. Human genome variation 7 28819563
2014 Identification of two novel mutations on CLCN7 gene in a patient with malignant ostopetrosis. Italian journal of pediatrics 7 25410126
2009 Refined genomic localization of the genetic lesion in the osteopetrosis (op) rat and exclusion of three positional and functional candidate genes, Clcn7, Atp6v0c, and Slc9a3r2. Calcified tissue international 7 19259722
2024 The Cl- transporter ClC-7 is essential for phagocytic clearance by microglia. Journal of cell science 6 38294065
2023 Distinct ClC-6 and ClC-7 Cl- sensitivities provide insight into ClC-7's role in lysosomal Cl- homeostasis. The Journal of physiology 6 37937509
2017 Novel mutations of CLCN7 cause autosomal dominant osteopetrosis type II (ADOII) and intermediate autosomal recessive osteopetrosis (ARO) in seven Chinese families. Postgraduate medicine 6 28975865
2018 CLCN7 and TCIRG1 mutations in a single family: Evidence for digenic inheritance of osteopetrosis. Molecular medicine reports 5 30431110
2015 Null mutation of chloride channel 7 (Clcn7) impairs dental root formation but does not affect enamel mineralization. Cell and tissue research 5 26346547
2008 CLCN7 polymorphisms and bone mineral density in healthy premenopausal white women and in white men. Bone 5 18755304
2020 Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis. Genes 4 33105733
2020 A Novel Variant in CLCN7 Regulates the Coupling of Angiogenesis and Osteogenesis. Frontiers in cell and developmental biology 4 33304905
2019 A Case of Autosomal Dominant Osteopetrosis Type 2 with a CLCN7 Gene Mutation. Journal of clinical research in pediatric endocrinology 4 30759959
2009 Osteopetrosis due to homozygous chloride channel ClCN7 mutation mimicking metabolic disease with haematological and neurological impairment. Klinische Padiatrie 4 19904698
2022 A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene. Calcified tissue international 3 35618777
2022 Autosomal dominant osteopetrosis type II resulting from a de novo mutation in the CLCN7 gene: A case report. World journal of clinical cases 3 36051116
2024 Effect of Allele-Specific Clcn7G213R siRNA Delivered Via a Novel Nanocarrier on Bone Phenotypes in ADO2 Mice on 129S Background. Calcified tissue international 2 38733412
2023 A novel compound heterozygous mutation of the CLCN7 gene is associated with autosomal recessive osteopetrosis. Frontiers in pediatrics 2 37168803
2018 Whole exome sequencing identified two novel homozygous missense variants in the same codon of CLCN7 underlying autosomal recessive infantile malignant osteopetrosis in a Pakistani family. Molecular biology reports 2 29926385
2025 Metabolomics study of osteopetrosis caused by CLCN7 mutation reveals novel pathway and potential biomarkers. Frontiers in endocrinology 1 40018371
2025 Identification of a novel mutation in the CLCN7 gene in pediatric osteopetrosis: case report. Frontiers in pediatrics 1 40276109
2024 Multisystem disorder associated with a pathogenic variant in CLCN7 in the absence of osteopetrosis. Molecular genetics & genomic medicine 1 39056574
2024 A 37-kb Deletion in Region 16p13.3 in an Infant with Osteopetrosis and Congenital Diarrhea Including the CLCN7 and PERCC1 Genes. Molecular syndromology 1 39359949
2021 Hematopoietic stem cell transplantation in a patient with osteopetrosis and mutation in CLCN7: long-term follow-up. Boletin medico del Hospital Infantil de Mexico 1 33651788
2018 Genetic Analysis of CLCN7 in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis. Endocrinology and metabolism (Seoul, Korea) 1 30229577
2026 CLC-7 Chloride Channels Affects rAAV Trafficking in Cells by Regulating Protease Activity in Lysosomes. Journal of medical virology 0 41674487
2025 The molecular and functional interplay between the osteopetrosis-associated proteins SNX10, OSTM1, and CLC-7 during mouse osteoclastogenesis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 0 41408708
2025 Novel de novo CLCN7 mutation in refractory osteopetrosis-related osteomyelitis: A case report and multidisciplinary therapeutic dilemmas. Journal of stomatology, oral and maxillofacial surgery 0 41421595
2025 Primate-specific sperm lnc-CLCN7 reveals embryo quality in IVF. Acta biochimica et biophysica Sinica 0 41466453
2012 A newly described mutation of the CLCN7 gene causes neuropathic autosomal recessive osteopetrosis in an Arab family. Clinical dysmorphology 0 21946807

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