Affinage

CLN3

Battenin · UniProt Q13286

Length
438 aa
Mass
47.6 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLN3 is a multipass transmembrane lysosomal glycoprotein whose loss causes Batten disease (juvenile neuronal ceroid lipofuscinosis), a fatal childhood neurodegenerative lysosomal storage disorder (PMID:7553855). Its primary established biochemical function is mediating lysosomal egress of glycerophosphodiesters, the end-products of glycerophospholipid catabolism, whose massive lysosomal accumulation in CLN3-deficient brain and cells defines the proximal metabolic defect (PMID:36131016). CLN3 additionally maintains lysosomal pH homeostasis, promotes mannose-6-phosphate receptor-dependent lysosomal enzyme sorting and autophagic lysosomal reformation, and supports microdomain-associated protein trafficking at the trans-Golgi network (PMID:10319861, PMID:37400440, PMID:24227717). The protein is sorted to lysosomes via dileucine and M(X)9G motifs recognized by AP-1 and AP-3 adaptors, is N-glycosylated at N71/N85, and is farnesylated at C435, with prenylation required for efficient lysosomal retention (PMID:14699076, PMID:15598649, PMID:17286803).

Mechanistic history

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

    Identification of CLN3 as the Batten disease gene resolved a decades-long search for the genetic basis of juvenile neuronal ceroid lipofuscinosis and revealed CLN3 encodes a novel 438-aa protein of unknown function.

    Evidence Exon amplification, genomic deletion mapping, and mutation identification in patient cohorts

    PMID:7553855

    Open questions at the time
    • No biochemical function assigned
    • Subcellular localization unknown
    • No animal model yet available
  2. 1999 High

    Establishing CLN3 as a lysosomal membrane protein and demonstrating that the common disease-causing deletion retains the protein in the ER provided a cellular framework for understanding pathogenesis and distinguished classical from atypical disease.

    Evidence Immunoelectron microscopy, pulse-chase labeling, and confocal microscopy in BHK cells, COS-1, HeLa, and primary neurons; ER retention of 461-677del mutant vs. lysosomal localization of E295K

    PMID:10332042 PMID:9384607

    Open questions at the time
    • Lysosomal function of CLN3 still unknown
    • Mechanism of ER retention of truncated mutant not defined
  3. 1999 High

    Demonstration that loss of the yeast CLN3 orthologue BTN1 causes abnormal vacuolar pH, rescued by human CLN3, established a conserved role in organellar pH homeostasis and provided the first functional assignment.

    Evidence Yeast genetic complementation and vacuolar pH measurement in btn1Δ S. cerevisiae; replicated in S. pombe

    PMID:10319861 PMID:16291725

    Open questions at the time
    • Direct mechanism of pH regulation unknown
    • Whether pH defect is primary or secondary to another function unclear
  4. 2003 High

    Mapping of CLN3 lysosomal targeting signals—dileucine and M(X)9G motifs—and identification of AP-1 and AP-3 as sorting adaptors defined the trafficking itinerary from the TGN through endosomes to lysosomes, with a transient plasma membrane pool.

    Evidence Motif mutagenesis, chimeric reporter assays, in vitro adaptor binding, AP-1/AP-3-deficient fibroblasts, and surface biotinylation

    PMID:14644441 PMID:14699076 PMID:15469932 PMID:15598649

    Open questions at the time
    • Relative contribution of direct vs. indirect sorting routes in neurons not resolved
    • Whether AP-1 and AP-3 act sequentially or in parallel at specific compartments debated
  5. 2003 High

    CLN3 topology was resolved as a five-transmembrane domain protein with a luminal N-terminus and cytoplasmic C-terminus, establishing the structural framework for understanding cytoplasmic motif function and lipid modification sites.

    Evidence In vitro translation with microsomes, glycosylation-site mutagenesis, and epitope accessibility assays

    PMID:12706816

    Open questions at the time
    • No high-resolution structure
    • How transmembrane segments contribute to function unknown
  6. 2007 High

    Discovery that CLN3 is farnesylated at C435 and that this modification promotes lysosomal retention revealed a post-translational mechanism governing CLN3 steady-state distribution, particularly in neurons.

    Evidence Mevalonate metabolic labeling, farnesyltransferase inhibitor treatment, C435 mutagenesis, and subcellular fractionation in neuronal and non-neuronal cells

    PMID:17286803

    Open questions at the time
    • How prenylation mechanistically anchors CLN3 in lysosomal membranes not determined
    • Functional consequence of surface-redirected CLN3 not fully explored
  7. 2007 Medium

    CLN3 was linked to lipid metabolism through its association with BMP synthesis and ceramide modulation, providing early evidence that CLN3 participates in lysosomal lipid homeostasis beyond pH control.

    Evidence DRM isolation, phospholipid analysis, metabolic labeling in JNCL fibroblasts and brain tissue; complementation with WT and L170P mutant CLN3

    PMID:10191118 PMID:17482562

    Open questions at the time
    • Whether CLN3 directly synthesizes or transports BMP is unclear
    • Ceramide modulation mechanism not defined
  8. 2011 Medium

    Studies in yeast placed BTN1/CLN3 at the Golgi where it regulates Sed5 SNARE phosphorylation via the kinase Yck3, controlling endosome-to-Golgi retrograde transport—expanding CLN3 function beyond the lysosome to the endosomal sorting network.

    Evidence Yeast genetics, SNARE complex pull-down, phosphorylation assays, and epistasis analysis

    PMID:21987636

    Open questions at the time
    • Whether mammalian CLN3 similarly regulates Golgi SNAREs is untested
    • Golgi localization of mammalian CLN3 not firmly established at this time
  9. 2013 High

    CLN3 was shown to function at the trans-Golgi network in microdomain-dependent trafficking of caveolin-1, syntaxin-6, and MDR1, with lactosylceramide supplementation rescuing defects, linking CLN3 to sphingolipid-dependent protein sorting.

    Evidence siRNA knockdown, subcellular fractionation, caveolae quantification, drug efflux assays, and sphingolipid rescue in brain endothelial cells

    PMID:24227717

    Open questions at the time
    • Whether CLN3 directly modifies lipid microdomain composition or acts indirectly unclear
    • Relevance to neuronal pathology not directly tested
  10. 2019 High

    Quantitative lysosomal proteomics in CLN3-deficient cells revealed broad depletion of soluble lysosomal hydrolases and lipid-degrading enzymes alongside altered membrane lipid composition, establishing that CLN3 loss causes a global lysosomal enzyme deficiency secondary to enzyme mis-sorting.

    Evidence SILAC-based quantitative proteomics of magnetically purified lysosomes, enzyme activity assays, and lipidomic analysis in cerebellar cells

    PMID:31040178

    Open questions at the time
    • Whether enzyme depletion is solely due to M6PR mis-trafficking or involves additional mechanisms
    • Which hydrolase deficiencies drive neurodegeneration
  11. 2021 High

    CLN3 localization to RPE microvilli and its requirement for photoreceptor outer segment phagocytosis provided a direct mechanistic explanation for the early visual loss in Batten disease patients.

    Evidence iPSC-derived RPE from patients, POS binding/ingestion assays, and gene rescue

    PMID:33547385

    Open questions at the time
    • Molecular mechanism of CLN3 in phagocytic cup formation not defined
    • Whether phagocytosis defect is secondary to lipid or trafficking defects unknown
  12. 2022 High

    Identification of glycerophosphodiesters as the primary substrates accumulating in CLN3-deficient lysosomes established CLN3 as a mediator of lysosomal GPD egress, providing the first direct biochemical function and a candidate biomarker for Batten disease.

    Evidence LysoTag mouse tissue-specific lysosome isolation, untargeted metabolomics, validation in CLN3-deficient cultured cells, and CSF glycerophosphoinositol measurement in patients

    PMID:36131016

    Open questions at the time
    • Whether CLN3 is a direct GPD transporter or recruits a transporter unknown
    • Structural basis for substrate recognition not determined
    • How GPD accumulation triggers neurodegeneration not established
  13. 2023 High

    Discovery that CLN3 physically interacts with CI-M6PR and is required for autophagic lysosomal reformation unified the enzyme mis-sorting and autophagy defects under a single trafficking mechanism.

    Evidence Proteomic interaction analysis, co-immunoprecipitation, CI-M6PR trafficking and lysosomal reformation assays with gain- and loss-of-function experiments

    PMID:37400440

    Open questions at the time
    • Structural interface between CLN3 and CI-M6PR not mapped
    • Whether ALR defect contributes to neurodegeneration independently of enzyme mis-sorting unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether CLN3 functions as a direct glycerophosphodiester transporter or acts indirectly, how GPD accumulation leads to selective neuronal vulnerability, and the high-resolution structure of CLN3 remain unknown.
  • No reconstituted transport assay with purified CLN3
  • No high-resolution structure
  • Mechanism linking GPD accumulation to neurodegeneration undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0008289 lipid binding 2
Localization
GO:0005764 lysosome 6 GO:0005768 endosome 3 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 2
Partners
CLN5HOOK1IGF2RKCNIP3RAB7ARILPSPTAN1
Complex memberships
CLN3-CLN5 endolysosomal complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CLN3 encodes a novel 438 amino acid protein; a 1 kb genomic deletion disrupting CLN3 is the causative mutation in the majority of Batten disease patients, identifying it as the Batten disease gene. Exon amplification, genomic deletion mapping, mutation identification in patients Cell High 7553855
1998 CLN3 protein is synthesized as an N-glycosylated ~43 kDa polypeptide and localizes to the lysosomal compartment in COS-1 and HeLa cells, establishing CLN3 as a lysosomal protein. In vitro translation, immunoprecipitation, Western blotting, pulse-chase experiments, confocal immunofluorescence microscopy Human molecular genetics High 9384607
1999 CLN3 localizes to the lysosomal membrane confirmed by immunoelectron microscopy co-localization with lysosomal markers; the common 461-677del mutant is retained in the ER while the E295K missense mutant reaches lysosomes, explaining classical vs. atypical JNCL. Immunoelectron microscopy, pulse-chase labeling, immunoprecipitation, transient expression in BHK cells and mouse primary neurons Human molecular genetics High 10332042
1999 Yeast BTN1 (orthologue of CLN3) deletion causes abnormally acidic vacuolar pH in early growth phases; human CLN3 complemented btn1-delta, demonstrating functional conservation and implicating CLN3 in vacuolar/lysosomal pH control. Yeast genetic complementation, vacuolar pH measurement, DNA microarray analysis Nature genetics High 10319861
2003 Vacuolar arginine transport requires functional BTN1/CLN3; btn1-delta yeast have decreased arginine transport into vacuoles due to altered vacuolar pH, and this defect is complemented by either BTN1 or human CLN3, implicating CLN3 in lysosomal basic amino acid transport or its regulation. Yeast vacuole isolation, ATP-dependent arginine transport assay, genetic complementation Proceedings of the National Academy of Sciences of the United States of America High 14660799
2003 CLN3 membrane topology was determined to contain five transmembrane domains, an extracellular/intraluminal amino-terminus, and a cytoplasmic carboxy-terminus. In vitro translation with canine pancreatic microsomes, Flag epitope tagging, glycosylation site mutagenesis, immunoprecipitation FEBS letters High 12706816
2003 CLN3 contains two lysosomal targeting motifs: an unconventional M(X)9G motif in the C-terminal cytosolic tail and a dileucine motif in the large cytosolic loop; both contribute to lysosomal targeting in non-neuronal and neuronal cells. In primary neurons, CLN3 also localizes to endosomes along neuronal processes independent of these targeting motifs. Mutagenesis of targeting motifs, transfection of non-neuronal and neuronal cells, immunofluorescence colocalization Molecular biology of the cell High 14699076
2004 A dileucine-based sorting motif (EEEX8LI) in the second cytoplasmic domain of CLN3 is sufficient for lysosomal targeting when fused to reporter proteins; none of the CLN3 cytoplasmic domains interact with AP-1, AP-3, or GGA3 adaptor complexes directly. Chimeric protein construction with LAMP-1 and lysosomal acid phosphatase reporters, transient transfection, immunofluorescence, adaptor complex binding assays The Journal of biological chemistry High 15469932
2004 The dileucine motif of CLN3 binds both AP-1 and AP-3 adaptor complexes in vitro; both AP-1- and AP-3-deficient mouse fibroblasts show missorting of CLN3, indicating sequential sorting via these adaptors. Biochemical binding assays, immunofluorescence in AP-1/AP-3 deficient fibroblasts The Journal of biological chemistry High 15598649
2004 CLN3 interacts with Hook1 protein; CLN3 overexpression induces Hook1 aggregation possibly by dissociating it from microtubules; in vitro binding demonstrates a weak interaction between Hook1 and cytoplasmic segments of CLN3. Receptor-mediated endocytosis is defective in CLN3-deficient JNCL fibroblasts. In vitro binding assay, Co-IP, overexpression studies, endocytosis assay in patient fibroblasts Human molecular genetics Medium 15471887
2002 CLN5 physically interacts with CLN3 based on co-immunoprecipitation and in vitro binding assays; this interaction occurs with the membrane-bound form of CLN5. Co-immunoprecipitation, in vitro binding assay Molecular biology of the cell Medium 12134079
1999 CLN3 overexpression in NT2 neuronal precursor cells protects against apoptosis induced by vincristine, staurosporine, and etoposide but not ceramide; CLN3 modulates endogenous ceramide levels and suppresses apoptosis upstream of ceramide generation. Overexpression in NT2 cells, apoptosis assays, ceramide modulation Molecular genetics and metabolism Medium 10191118
2007 CLN3 is prenylated (most likely farnesylated) at cysteine 435 via a C-terminal CAAX motif; substitution of C435 reduces steady-state lysosomal levels of CLN3 and increases its surface expression, particularly in neuronal cells. Mevalonate incorporation, farnesyltransferase inhibitor studies, C435 mutagenesis, subcellular fractionation/immunofluorescence Traffic (Copenhagen, Denmark) High 17286803
2007 CLN3 is glycosylated at asparagine residues N71 and N85; both partially and non-glycosylated CLN3 are transported correctly to lysosomes, indicating glycosylation is not required for lysosomal targeting. Mutational analysis of glycosylation sites, COS7 cell transfection, immunofluorescence Traffic (Copenhagen, Denmark) Medium 17286803
2008 CLN3 interacts with fodrin (alpha-spectrin) and the associated Na+/K+ ATPase; CLN3 deficiency leads to abnormal fodrin immunostaining and disturbed subcellular distribution and ouabain-induced endocytosis of Na+/K+ ATPase in mouse primary neurons. Co-immunoprecipitation, immunostaining in Cln3-/- mouse primary neurons and JNCL fibroblasts, Na+/K+ ATPase activity assay Experimental cell research Medium 18621045
2012 CLN3 interacts with motor proteins tubulin, dynactin, dynein, and kinesin-2, and directly interacts with GTP-bound (active) Rab7 and RILP; CLN3E295K overexpression causes perinuclear clustering of late endosomes/lysosomes, and CLN3 deficiency impairs anterograde transport of late endosomal/lysosomal compartments. Co-immunoprecipitation, pull-down assays with GTP-bound Rab7, overexpression studies in HeLa cells, live cell imaging Cellular and molecular life sciences : CMLS Medium 22261744
2005 In S. pombe, btn1 (CLN3 orthologue) deletion causes enlarged, alkaline vacuoles; btn1 overexpression reduces vacuole diameter and pH; human CLN3 rescues btn1 deletion phenotypes, confirming functional conservation; Btn1p localizes to the vacuole membrane via endocytic/pre-vacuolar compartments, dependent on Ypt7p. Genetic deletion and overexpression, vacuolar pH measurement, heterologous complementation, fluorescence microscopy Journal of cell science High 16291725
2007 CLN3 associates with bis(monoacylglycerol)phosphate (BMP) synthesis; JNCL patient brain and fibroblasts show reduced BMP in detergent-resistant membranes; wild-type CLN3 complementation restores BMP synthesis, and CLN3-L170P mutant decreases BMP synthesis. DRM isolation, phospholipid analysis, metabolic labeling, complementation with WT and mutant CLN3 Biochemical and biophysical research communications Medium 17482562
2011 In Drosophila, CLN3 genetically interacts with core stress signaling pathways and components of stress granules; CLN3 mutant flies are hypersensitive to oxidative stress and unable to detoxify reactive oxygen species, while CLN3 overexpression confers increased resistance to oxidative stress. Gain-of-function modifier screen in Drosophila, oxidative stress survival assays, genetic epistasis Human molecular genetics Medium 21372148
2011 In yeast, BTN1 (CLN3 orthologue) localizes to the Golgi and regulates SNARE function for endosome-to-Golgi retrograde transport by modulating phosphorylation of the Sed5 t-SNARE via regulation of the palmitoylated endosomal kinase Yck3. Yeast genetics, localization studies, SNARE complex pull-down, phosphorylation assays, epistasis analysis The Journal of cell biology Medium 21987636
2006 CLN3 interacts with calsenilin (DREAM/KChIP3) via its C-terminal region; Ca2+ elevation dissociates calsenilin from CLN3; CLN3 C-terminus expression suppresses Ca2+-induced neuronal cell death, while CLN3 deletion mutants lacking this region fail to inhibit cell death and perturb Ca2+ transients. In vitro binding assay, co-immunoprecipitation, overexpression/deletion mutant analysis, calcium imaging, neuronal death assays Human molecular genetics Medium 17189291
2013 CLN3 is required for normal trafficking of caveolin-1, syntaxin-6, and MDR1 in brain endothelial cells; CLN3-null cells have reduced caveolae, impaired caveolae-mediated endocytosis and drug efflux; CLN3 localizes to the trans-Golgi network and partitions with buoyant microdomain fractions; lactosylceramide application rescues protein transport in CLN3-deficient cells. siRNA knockdown, immunofluorescence, caveolae quantification, functional endocytosis/drug efflux assays, subcellular fractionation, fluorescent sphingolipid probes The Journal of neuroscience : the official journal of the Society for Neuroscience High 24227717
2019 CLN3-deficient cerebellar cells show reduced abundance of 28 soluble lysosomal hydrolases and 11 lipid-degrading lysosomal enzymes, decreased capacity for lipid droplet degradation, altered membrane lipid composition (reduced lactosylceramides and glycosphingolipids), and impaired recycling endosome pathway for transferrin receptor. SILAC-based quantitative proteomics of magnetically purified lysosomes, immunoblotting, enzyme activity assays, lipidomic analysis The Journal of biological chemistry High 31040178
2022 CLN3 is required for lysosomal egress of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism; loss of CLN3 causes massive lysosomal accumulation of GPDs in mouse brain and CLN3-deficient cultured cells; CLN3 deficiency also disrupts glycerophospholipid catabolism in lysosomes; glycerophosphoinositol is elevated in CSF of Batten disease patients. LysoTag mouse for tissue-specific lysosome isolation, untargeted metabolite profiling, CLN3-deficient cultured cell validation, CSF analysis from patients Nature High 36131016
2021 CLN5 and CLN3 function as an endolysosomal complex; CLN5 deletion results in impaired endolysosome fusion and defective autophagy by modulating interactions between CLN3, RAB7A, and RAB7A effectors. Co-immunoprecipitation, endolysosome fusion assays, autophagy flux assays, RAB7A effector interaction studies The Biochemical journal Medium 34060589
2023 CLN3 interacts with the cation-independent mannose 6-phosphate receptor (CI-M6PR); CLN3 depletion causes mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation; CLN3 overexpression promotes lysosomal tubule formation in a CI-M6PR- and autophagy-dependent manner. Proteomic analysis, co-immunoprecipitation, CI-M6PR trafficking assays, lysosomal reformation assays, overexpression and knockdown experiments Nature communications High 37400440
2003 Endogenous CLN3 traffics to the lysosome via the plasma membrane; surface biotinylation and antibody trapping in NCCIT cells demonstrated that a proportion of CLN3 reaches the cell surface en route to the lysosome; inhibition of AP-3 adaptor subunit mu3A increases CLN3 at the cell surface. Surface biotinylation, antibody trapping, AP-3 subunit knockdown in NCCIT cells FEBS letters Medium 14644441
2021 CLN3 in human, mouse, and iPSC-derived RPE cells localizes to RPE microvilli; CLN3 disease iPSC-RPE cells show decreased RPE microvilli density and reduced photoreceptor outer segment (POS) binding and ingestion; POS phagocytosis defect is rescued by wild-type CLN3 gene supplementation. iPSC-derived RPE cells from patients, immunofluorescence localization, POS binding/ingestion phagocytosis assay, gene rescue Communications biology High 33547385

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell 460 7553855
1993 Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. The EMBO journal 429 8387915
1992 The Cln3-Cdc28 kinase complex of S. cerevisiae is regulated by proteolysis and phosphorylation. The EMBO journal 384 1316273
1995 p34Cdc28-mediated control of Cln3 cyclin degradation. Molecular and cellular biology 271 7823941
1997 Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast. Genes & development 248 9334317
1997 Spectrum of mutations in the Batten disease gene, CLN3. American journal of human genetics 178 9311735
1998 Biosynthesis and intracellular targeting of the CLN3 protein defective in Batten disease. Human molecular genetics 163 9384607
2002 Cln3(Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Human molecular genetics 161 12374761
1999 Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Nature genetics 149 10319861
2004 Interconnections of CLN3, Hook1 and Rab proteins link Batten disease to defects in the endocytic pathway. Human molecular genetics 121 15471887
2005 Production, purification, and characterization of lipase from thermophilic and alkaliphilic Bacillus coagulans BTS-3. Protein expression and purification 107 15802219
2022 CLN3 is required for the clearance of glycerophosphodiesters from lysosomes. Nature 106 36131016
1990 Batten disease (Spielmeyer-Vogt disease, juvenile onset neuronal ceroid-lipofuscinosis) gene (CLN3) maps to human chromosome 16. Genomics 104 2249854
2005 CLN3, the protein associated with batten disease: structure, function and localization. Journal of neuroscience research 100 15657902
1999 Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Human molecular genetics 99 10332042
2003 Two motifs target Batten disease protein CLN3 to lysosomes in transfected nonneuronal and neuronal cells. Molecular biology of the cell 97 14699076
1998 Regulation of the Cln3-Cdc28 kinase by cAMP in Saccharomyces cerevisiae. The EMBO journal 96 9687505
2002 Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Molecular biology of the cell 90 12134079
2003 A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease. Proceedings of the National Academy of Sciences of the United States of America 89 14660799
2007 Cyclin Cln3 is retained at the ER and released by the J chaperone Ydj1 in late G1 to trigger cell cycle entry. Molecular cell 87 17560371
1999 CLN3 defines a novel antiapoptotic pathway operative in neurodegeneration and mediated by ceramide. Molecular genetics and metabolism 86 10191118
2005 New assays for detection and localization of endogenous lipid peroxidation products in living boar sperm after BTS dilution or after freeze-thawing. Theriogenology 85 15626411
2009 Recruitment of Cln3 cyclin to promoters controls cell cycle entry via histone deacetylase and other targets. PLoS biology 83 19823669
2013 Alterations in ROS activity and lysosomal pH account for distinct patterns of macroautophagy in LINCL and JNCL fibroblasts. PloS one 80 23408996
2000 Batten disease: evaluation of CLN3 mutations on protein localization and function. Human molecular genetics 79 10749980
2002 The G(1) cyclin Cln3 promotes cell cycle entry via the transcription factor Swi6. Molecular and cellular biology 78 12024050
1993 The yeast Cln3 protein is an unstable activator of Cdc28. Molecular and cellular biology 75 8497251
2005 btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis. Journal of cell science 69 16291725
1996 A model for Batten disease protein CLN3: functional implications from homology and mutations. FEBS letters 68 8980123
2007 A function retained by the common mutant CLN3 protein is responsible for the late onset of juvenile neuronal ceroid lipofuscinosis. Human molecular genetics 67 17947292
2012 Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments. Cellular and molecular life sciences : CMLS 66 22261744
1997 Immunochemical localization of the Batten disease (CLN3) protein in retina. Investigative ophthalmology & visual science 66 9344361
2019 The CLN3 gene and protein: What we know. Molecular genetics & genomic medicine 64 31568712
2001 Osmotic stress causes a G1 cell cycle delay and downregulation of Cln3/Cdc28 activity in Saccharomyces cerevisiae. Molecular microbiology 64 11251821
1999 Genetic analysis of the shared role of CLN3 and BCK2 at the G(1)-S transition in Saccharomyces cerevisiae. Genetics 64 10545447
2006 Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal, and synaptic compartments. Journal of neuroscience research 62 16941499
2005 The G1 cyclin Cln3 regulates morphogenesis in Candida albicans. Eukaryotic cell 59 15643064
2016 Self-Complementary AAV9 Gene Delivery Partially Corrects Pathology Associated with Juvenile Neuronal Ceroid Lipofuscinosis (CLN3). The Journal of neuroscience : the official journal of the Society for Neuroscience 57 27629717
2000 The yeast model for batten disease: mutations in BTN1, BTN2, and HSP30 alter pH homeostasis. Journal of bacteriology 57 11053386
2002 Retinal pathology and function in a Cln3 knockout mouse model of juvenile Neuronal Ceroid Lipofuscinosis (batten disease). Molecular and cellular neurosciences 56 11988019
2011 Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit C accumulation in cerebellar cells. PloS one 55 21359198
2012 Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PloS one 54 22701626
2002 Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Annals of neurology 54 11921051
2002 AZF1 is a glucose-dependent positive regulator of CLN3 transcription in Saccharomyces cerevisiae. Molecular and cellular biology 52 11839825
2013 CLN3 loss disturbs membrane microdomain properties and protein transport in brain endothelial cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 24227717
2004 A dileucine motif and a cluster of acidic amino acids in the second cytoplasmic domain of the batten disease-related CLN3 protein are required for efficient lysosomal targeting. The Journal of biological chemistry 51 15469932
2004 AP-1 and AP-3 facilitate lysosomal targeting of Batten disease protein CLN3 via its dileucine motif. The Journal of biological chemistry 50 15598649
1995 Batten disease gene, CLN3: linkage disequilibrium mapping in the Finnish population, and analysis of European haplotypes. American journal of human genetics 50 7887419
1993 Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci. Genomics 50 8314582
1999 Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Human mutation 49 10477428
1991 Regional mapping of the Batten disease locus (CLN3) to human chromosome 16p12. American journal of human genetics 49 1746562
2019 Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking. The Journal of biological chemistry 48 31040178
2014 Evidence for aberrant astrocyte hemichannel activity in Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). PloS one 48 24736558
2004 Boar sperm storage capacity of BTS and Androhep Plus: viability, motility, capacitation, and tyrosine phosphorylation. Theriogenology 47 15251239
2019 Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy. Ophthalmology. Retina 46 31926949
2020 Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease. Nature medicine 45 32719489
2011 The Batten disease gene CLN3 is required for the response to oxidative stress. Human molecular genetics 45 21372148
2011 Analysis of potential biomarkers and modifier genes affecting the clinical course of CLN3 disease. Molecular medicine (Cambridge, Mass.) 45 21863212
2004 A cell sizer network involving Cln3 and Far1 controls entrance into S phase in the mitotic cycle of budding yeast. The Journal of cell biology 45 15520229
2002 The CLN3 gene is a novel molecular target for cancer drug discovery. Cancer research 45 11830536
2001 Early cell cycle box-mediated transcription of CLN3 and SWI4 contributes to the proper timing of the G(1)-to-S transition in budding yeast. Molecular and cellular biology 45 11390643
1998 Cln3-associated kinase activity in Saccharomyces cerevisiae is regulated by the mating factor pathway. Molecular and cellular biology 45 9418890
2019 Knockdown of BTS may provide a new strategy to improve cadmium-phytoremediation efficiency by improving iron status in plants. Journal of hazardous materials 44 31676164
2006 Neuronal vulnerability of CLN3 deletion to calcium-induced cytotoxicity is mediated by calsenilin. Human molecular genetics 44 17189291
2014 Loss of Cln3 function in the social amoeba Dictyostelium discoideum causes pleiotropic effects that are rescued by human CLN3. PloS one 42 25330233
2008 Novel interactions of CLN3 protein link Batten disease to dysregulation of fodrin-Na+, K+ ATPase complex. Experimental cell research 42 18621045
1997 Genomic structure and complete nucleotide sequence of the Batten disease gene, CLN3. Genomics 42 9119403
2011 The yeast Batten disease orthologue Btn1 controls endosome-Golgi retrograde transport via SNARE assembly. The Journal of cell biology 41 21987636
2003 Membrane topology of CLN3, the protein underlying Batten disease. FEBS letters 41 12706816
1998 Growth-independent regulation of CLN3 mRNA levels by nutrients in Saccharomyces cerevisiae. Journal of bacteriology 41 9440509
2021 Repurposing of tamoxifen ameliorates CLN3 and CLN7 disease phenotype. EMBO molecular medicine 40 34411438
2013 Drafting the CLN3 protein interactome in SH-SY5Y human neuroblastoma cells: a label-free quantitative proteomics approach. Journal of proteome research 40 23464991
2002 The CLN3/SWI6/CLN2 pathway and SNF1 act sequentially to regulate meiotic initiation in Saccharomyces cerevisiae. Genes to cells : devoted to molecular & cellular mechanisms 40 12081645
2023 Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation. Nature communications 39 37400440
2007 A novel role of the Batten disease gene CLN3: association with BMP synthesis. Biochemical and biophysical research communications 39 17482562
2017 Homeostatic control of START through negative feedback between Cln3-Cdk1 and Rim15/Greatwall kinase in budding yeast. eLife 35 28600888
2008 btn1 affects endocytosis, polarization of sterol-rich membrane domains and polarized growth in Schizosaccharomyces pombe. Traffic (Copenhagen, Denmark) 35 18346214
2016 Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Annals of the New York Academy of Sciences 34 26748992
2021 A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor-RPE interface. Communications biology 33 33547385
2016 Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Annals of neurology 33 27804148
2007 C-terminal prenylation of the CLN3 membrane glycoprotein is required for efficient endosomal sorting to lysosomes. Traffic (Copenhagen, Denmark) 33 17286803
1998 Transcriptional regulation of CLN3 expression by glucose in Saccharomyces cerevisiae. Journal of bacteriology 33 9721289
2020 Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium. Biochimica et biophysica acta. Molecular basis of disease 31 32592935
2008 Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models. Human molecular genetics 31 18678598
2017 Loss of Cln3 impacts protein secretion in the social amoeba Dictyostelium. Cellular signalling 30 28365442
2007 Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue. Journal of neurochemistry 30 17868323
1998 Molecular screening of Batten disease: identification of a missense mutation (E295K) in the CLN3 gene. Human genetics 30 9490299
2016 Using Patient-Specific Induced Pluripotent Stem Cells and Wild-Type Mice to Develop a Gene Augmentation-Based Strategy to Treat CLN3-Associated Retinal Degeneration. Human gene therapy 29 27400765
2014 Novel CLN3 mutation causing autophagic vacuolar myopathy. Neurology 29 24827497
2008 Btn1 affects cytokinesis and cell-wall deposition by independent mechanisms, one of which is linked to dysregulation of vacuole pH. Journal of cell science 28 18697832
1999 Phenotypic reversal of the btn1 defects in yeast by chloroquine: a yeast model for Batten disease. Proceedings of the National Academy of Sciences of the United States of America 28 10500178
1996 Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3. Genomics 27 8812504
2021 CLN3, at the crossroads of endocytic trafficking. Neuroscience letters 26 34274435
2016 Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease). PloS one 26 27327661
2021 CLN5 and CLN3 function as a complex to regulate endolysosome function. The Biochemical journal 25 34060589
2013 Methodology of clinical research in rare diseases: development of a research program in juvenile neuronal ceroid lipofuscinosis (JNCL) via creation of a patient registry and collaboration with patient advocates. Contemporary clinical trials 24 23628560
2003 Intracellular trafficking of CLN3, the protein underlying the childhood neurodegenerative disease, Batten disease. FEBS letters 24 14644441
2000 Neural and extraneural expression of the neuronal ceroid lipofuscinoses genes CLN1, CLN2, and CLN3: functional implications for CLN3. Molecular genetics and metabolism 24 11001812
2018 Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities. Journal of neurochemistry 23 29964296
1998 Studies of atypical JNCL suggest overlapping with other NCL forms. Pediatric neurology 23 9492089