Affinage

CLN5

Bis(monoacylglycero)phosphate synthase CLN5 · UniProt O75503

Length
358 aa
Mass
41.5 kDa
Annotated
2026-04-28
89 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLN5 is a soluble lysosomal glycoprotein that functions as the BMP (bis(monoacylglycero)phosphate) synthase, catalyzing an energy-independent base exchange reaction between two lysophosphatidylglycerol molecules, and additionally possesses cysteine palmitoyl thioesterase (S-depalmitoylase) activity mediated by a Cys280-His166-Glu183 catalytic triad within an NlpC/P60 superfamily fold (PMID:37708259, PMID:35427157). Synthesized as a type II transmembrane precursor, CLN5 is cleaved by the intramembrane protease SPPL3 to yield a mature soluble form (residues 93–407) that is retained in the lysosomal lumen via an amphipathic helix and trafficked through both mannose-6-phosphate receptor-dependent and -independent pathways (PMID:28442266, PMID:24038957, PMID:20052765). CLN5 forms an endolysosomal complex with CLN3 that controls RAB7A-dependent retromer recruitment, endolysosome fusion, and stability of the sorting receptors sortilin and CI-MPR; its protein levels are regulated by KCTD7–CUL3 ubiquitin ligase-mediated proteasomal degradation, and excess CLN5 disrupts CLN6/CLN8-dependent ER-to-Golgi trafficking of lysosomal enzymes (PMID:34060589, PMID:22431521, PMID:35921411). Loss-of-function mutations in CLN5 cause Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL), characterized by accumulation of autofluorescent storage material and progressive cortical neurodegeneration (PMID:9662406, PMID:15459177).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 High

    Positional cloning established CLN5 as a novel disease gene, answering the molecular basis of Finnish variant late infantile neuronal ceroid lipofuscinosis and enabling all subsequent functional studies.

    Evidence Linkage analysis and mutation sequencing in Finnish vLINCL families identified three causative mutations

    PMID:9662406

    Open questions at the time
    • No protein characterization or subcellular localization
    • Function of the gene product entirely unknown
    • Original transmembrane topology prediction was later revised
  2. 2002 High

    Biochemical and localization studies overturned the initial transmembrane protein prediction, establishing CLN5 as a soluble lysosomal glycoprotein that physically interacts with CLN2 and CLN3, placing it within the NCL protein network.

    Evidence Confocal microscopy, deglycosylation, and reciprocal co-immunoprecipitation plus in vitro binding assays in BHK-21 and COS-1 cells

    PMID:11971870 PMID:12134079

    Open questions at the time
    • Enzymatic function unknown
    • Molecular basis for interactions with CLN2/CLN3 undefined
    • Contribution of different initiator methionines to function unclear
  3. 2004 High

    The Cln5 knockout mouse recapitulated human disease features—storage material accumulation, cortical neurodegeneration, and vision loss—providing a functional model and demonstrating that CLN5 is essential for neuronal survival in defined brain regions.

    Evidence Targeted exon 3 deletion in mice; electron microscopy, immunohistochemistry, and transcript profiling

    PMID:15207259 PMID:15459177

    Open questions at the time
    • Biochemical substrate or enzymatic activity of CLN5 still unknown
    • Mechanism linking CLN5 loss to storage material accumulation undefined
    • Why certain neuron populations are selectively vulnerable unclear
  4. 2009 Medium

    Expanding the NCL interactome, CLN5 was shown to interact with CLN1/PPT1, CLN6, and CLN8, and the distinctive cortex-first pattern of neurodegeneration in Cln5−/− mice was delineated, distinguishing CLN5 disease pathology from other NCL subtypes.

    Evidence Co-immunoprecipitation for interaction network; stereological analysis of neurodegeneration across disease stages in Cln5−/− mice

    PMID:19385065 PMID:19941651

    Open questions at the time
    • Functional significance of each NCL protein interaction not resolved
    • Whether interactions are direct or within larger complexes not determined for all partners
    • Molecular link between CLN5 and neurodegeneration pattern unknown
  5. 2012 High

    CLN5 was positioned as a regulator of endosomal sorting: its depletion reduced GTP-Rab7 and caused degradation of lysosomal sorting receptors sortilin and CI-MPR through defective retromer recruitment, providing the first mechanistic link between CLN5 and membrane trafficking.

    Evidence siRNA knockdown in HeLa cells with co-immunoprecipitation, Rab7 activation assay, and retromer recruitment analysis

    PMID:22431521

    Open questions at the time
    • Whether CLN5 acts directly on Rab7 or via an intermediary unknown
    • How CLN5 enzymatic activity relates to retromer function not established
    • Lipid perturbations in CLN5-deficient cells observed but not explained mechanistically
  6. 2013 High

    The biosynthetic processing of CLN5 was resolved: it is synthesized as a type II transmembrane protein whose N-terminal and TM domains are removed, yielding a soluble luminal protein anchored by an amphipathic helix; all eight N-glycosylation sites are utilized with differential roles in folding versus lysosomal targeting.

    Evidence Systematic mutagenesis of glycosylation sites and topology mapping with protease protection in transfected cells

    PMID:24038957 PMID:24058541

    Open questions at the time
    • Identity of the protease generating the mature form not yet established
    • Whether amphipathic helix mediates membrane interactions relevant to enzymatic function unknown
  7. 2017 Medium

    Two key advances: SPPL3 was identified as the intramembrane protease cleaving CLN5's transmembrane precursor to generate the mature soluble form, and the first enzymatic activity—glycoside hydrolase activity—was demonstrated for both Dictyostelium and human CLN5.

    Evidence SPPL family overexpression/inhibitor studies; glycoside hydrolase assay with purified protein and mass spectrometry-based interactomics

    PMID:28442266 PMID:29128403

    Open questions at the time
    • Physiological glycoside hydrolase substrates not identified
    • Whether glycoside hydrolase activity is the primary function in mammalian lysosomes unknown
    • SPPL3 cleavage not yet demonstrated with endogenous expression levels
  8. 2021 High

    CLN5 and CLN3 were shown to form a functional endolysosomal complex that controls RAB7A interactions with effectors and endolysosome fusion, directly linking CLN5 to the autophagy–lysosomal degradation axis and explaining trafficking defects in disease.

    Evidence CRISPR knockout, co-immunoprecipitation, endosome fusion assays, and CRISPRi in iPSC-derived neurons

    PMID:34060589 PMID:34680045

    Open questions at the time
    • Stoichiometry and structure of CLN3–CLN5 complex unknown
    • Whether enzymatic activity of CLN5 is required for complex function not tested
    • Relative contributions of BMP synthesis versus trafficking roles to disease pathology unclear
  9. 2022 High

    The crystal structure revealed CLN5 as an NlpC/P60 superfamily thioesterase with S-depalmitoylase activity via a Cys280-His166 catalytic dyad, and independently, CLN5 was identified as a substrate of the CRL3-KCTD7 ubiquitin ligase whose turnover controls ER-to-Golgi trafficking of lysosomal enzymes via CLN6/CLN8.

    Evidence X-ray crystallography and fluorescent thioesterase assay with active-site mutagenesis; ubiquitination assays and KCTD7 knockout cell analysis

    PMID:35427157 PMID:35921411

    Open questions at the time
    • Physiological depalmitoylation substrates not identified
    • Whether thioesterase and BMP synthase activities use the same active site not resolved
    • Structural basis of KCTD7-CLN5 recognition unknown
  10. 2023 High

    CLN5 was definitively identified as the lysosomal BMP synthase, resolving a decades-long search for this enzyme: it catalyzes BMP synthesis via energy-independent transacylation between two LPG molecules, and its loss causes massive LPG accumulation with BMP depletion.

    Evidence Lipidomics of CLN5 knockout cells and in vitro enzymatic reconstitution with purified protein

    PMID:37708259

    Open questions at the time
    • How BMP synthesis deficiency leads to the storage material accumulation and neurodegeneration not mechanistically defined
    • Whether BMP synthase and thioesterase activities are independent or share a catalytic mechanism unresolved
    • Regulation of BMP synthase activity in vivo poorly understood

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the relationship between CLN5's dual enzymatic activities (BMP synthase and thioesterase), identification of physiological depalmitoylation substrates, and how loss of BMP synthesis drives the selective neuronal vulnerability characteristic of CLN5 disease.
  • No study has tested whether the same catalytic site mediates both BMP synthesis and depalmitoylation
  • Endogenous thioesterase substrates remain unidentified
  • Mechanism linking BMP depletion to storage material formation and neurodegeneration not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1 GO:0016740 transferase activity 1
Localization
GO:0005764 lysosome 6 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005576 extracellular region 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 2 R-HSA-9612973 Autophagy 2 R-HSA-392499 Metabolism of proteins 1
Partners
CLN1CLN2CLN3CLN6CLN8KCTD7SORT1SPPL3
Complex memberships
CLN3-CLN5 endolysosomal complexCRL3-KCTD7 (as substrate)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 CLN5 was identified as a novel gene encoding a putative transmembrane protein underlying Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL), with three disease-causing mutations (one deletion, one nonsense, one missense) identified by positional cloning and sequence analysis. Positional cloning, linkage analysis, mutation sequencing Nature genetics High 9662406
2002 CLN5 protein localizes predominantly to lysosomes and is a soluble lysosomal glycoprotein (~60 kDa, reduced to ~40 kDa by deglycosylation), not an integral transmembrane protein as originally predicted; the most common human vLINCL mutation blocks lysosomal targeting. Confocal immunofluorescence microscopy, immunoprecipitation, deglycosylation assays, transient transfection in BHK-21 cells Human molecular genetics High 11971870
2002 CLN5 protein directly interacts with CLN2 and CLN3 proteins; CLN5 is synthesized as four precursor forms due to alternative initiator methionines, all targeted to lysosomes, with the longest membrane-associated form mediating interactions with CLN2 and CLN3; disease mutations in CLN5 abolished interaction with CLN2 but not CLN3. Coimmunoprecipitation, in vitro binding assays, western blotting Molecular biology of the cell High 12134079
2009 CLN5 interacts with multiple NCL proteins (CLN1/PPT1, CLN2/TPP1, CLN3, CLN6, CLN8); overexpression of PPT1 can facilitate lysosomal transport of mutated CLN5 normally retained in ER/Golgi; CLN5 also binds F1-ATPase, a known PPT1 binding partner. Coimmunoprecipitation, confocal microscopy, overexpression studies BMC cell biology Medium 19941651
2012 CLN5 interacts with the lysosomal sorting receptor sortilin; CLN5 depletion causes degradation of lysosomal sorting receptors sortilin and CI-MPR due to defective retromer recruitment at endosomes, linked to reduced active (GTP-loaded) Rab7 levels. Coimmunoprecipitation, siRNA knockdown in HeLa cells, western blotting, immunofluorescence Molecular and cellular biology High 22431521
2013 All eight N-glycosylation sites of CLN5 are utilized in vivo; glycosylation at N179, N252, N304, or N320 is required for proper protein folding (mutation causes ER retention), while N401 glycosylation is essential for lysosomal trafficking but not folding. Site-directed mutagenesis of individual Asn residues, localization studies by immunofluorescence, western blotting PloS one High 24058541
2013 CLN5 is synthesized as a type II transmembrane glycoprotein with cytoplasmic N-terminus, one TM segment, and a large luminal C-terminal domain containing an amphipathic helix (AH); cytoplasmic and TM domains are removed after signal peptide cleavage; the AH anchors mature CLN5 to the membrane lumen; CLN5 pathological mutants lacking AH are retained in the ER and degraded by the proteasome. Epitope-tagged CLN5 topology determination, protease protection assay, mutagenesis, immunofluorescence, proteasome inhibition Human mutation High 24038957
2015 CLN5 undergoes proteolytic C-terminal cleavage post-translationally in an acidic compartment, likely by a cysteine protease; two forms (~60 and ~56 kDa) are present in cells; processing occurs beyond the ER and can initiate from the trans-Golgi network. Cycloheximide chase analysis, pharmacological inhibition of proteases, transient transfection, western blotting Experimental cell research Medium 26342652
2017 CLN5 is cleaved by SPPL3 (a member of the SPP/SPPL intramembrane protease family), generating a mature soluble protein consisting of residues 93-407; the remaining N-terminal fragment is then cleaved by SPPL3 and SPPL2b and degraded by the proteasome. Overexpression of SPPL family members, inhibitor studies, western blotting, immunofluorescence Experimental cell research Medium 28442266
2017 Both Dictyostelium Cln5 and human CLN5 function as glycoside hydrolases, providing the first molecular enzymatic function attributed to CLN5; Dictyostelium Cln5 is secreted during growth and starvation; Cln5 immunoprecipitation identified 61 interacting proteins enriched for metabolic, catabolic, and hydrolytic functions including NCL-like proteins. Glycoside hydrolase enzymatic assay, immunoprecipitation coupled with mass spectrometry, localization by fluorescence microscopy, secretion assay Cellular signalling Medium 29128403
2018 A CLN5 missense variant (p.Asn320Ser) linked to Alzheimer's disease causes glycosylation defects leading to ER retention of CLN5 and reduced delivery to endolysosomal compartment; this variant reduces normal cathepsin D processing and decreases full-length APP levels, consistent with a retromer trafficking defect. Expression of mutant protein, glycosylation analysis, immunofluorescence localization, western blotting for cathepsin D maturation and APP levels Molecular and cellular biology Medium 30037983
2021 CLN5 and CLN3 function as an endolysosomal complex; CLN5 deletion causes retromer dysfunction and impaired endolysosome fusion, leading to delayed degradation of endocytic proteins and defective autophagy; CLN5 regulates CLN3 interactions with RAB7A and a subset of RAB7A effectors. CRISPR knockout, Co-IP, endosome fusion assays, western blotting, immunofluorescence The Biochemical journal High 34060589
2022 CLN5 (Cln5) crystal structure was solved and revealed a region homologous to the catalytic domain of N1pC/P60 superfamily papain-like enzymes; CLN5 has cysteine palmitoyl thioesterase (S-depalmitoylation) activity; the catalytic residues histidine-166 and cysteine-280 are critical for this activity; CLN5-deficient neuronal progenitor cells showed reduced thioesterase activity. X-ray crystallography, fluorescent substrate thioesterase assay, active-site mutagenesis, cell-based thioesterase activity assay Science advances High 35427157
2022 The CRL3-KCTD7 E3 ubiquitin ligase complex ubiquitinates CLN5 targeting it for proteasomal degradation; NCL patient-derived KCTD7 mutations disrupt KCTD7-CLN5 interaction causing CLN5 accumulation in the ER; excess CLN5 disrupts CLN6/CLN8 interaction with lysosomal enzymes, impairing ER-to-Golgi trafficking of lysosomal enzymes. Co-IP, ubiquitination assays, KCTD7 knockout cells, western blotting, immunofluorescence Science advances High 35921411
2023 CLN5 is the lysosomal BMP (bis(monoacylglycero)phosphate) synthase; CLN5-deficient cells show massive accumulation of the BMP synthesis precursor LPG and depletion of BMP species; CLN5 mediates BMP synthesis through an energy-independent base exchange reaction between two LPG molecules, with increased activity on BMP-laden vesicles. Lipidomics of CLN5 knockout cells, in vitro enzymatic reconstitution with purified protein, lipid mass spectrometry Science (New York, N.Y.) High 37708259
2023 QM/MM computational analysis confirmed the catalytic triad Cys280-His166-Glu183 is critical for CLN5 S-depalmitoylation activity; the S-depalmitoylation step is rate-limiting with a barrier of ~26.1 kcal/mol; this study defined the atomic-level reaction mechanism. QM/MM molecular dynamics at ωB97X-D/6-31G(d,p):AMBER level, NBO charge analysis, local mode force constants Journal of the American Chemical Society Medium 38055807
2010 CLN5 is proteolytically cleaved to produce a mature polypeptide trafficked to lysosomes; CLN5 can undergo mannose-6-phosphate receptor-independent trafficking to lysosomes; all analyzed disease mutations disturb lysosomal trafficking of CLN5 but the degree of lysosomal targeting does not correlate with disease onset, suggesting CLN5 may also function outside lysosomes. Stable and transient expression, immunofluorescence localization, western blotting, treatment with M6P receptor inhibitors Human mutation Medium 20052765
2012 CLN5-deficient fibroblasts show reduced ceramide, sphingomyelin, and glycosphingolipid levels; CLN8 protein corrects growth and apoptosis defects in CLN5-deficient cells; co-immunoprecipitation with CerS1 and absence of γ-actin from the CerS1 protein complex in CLN5-deficient cells suggest CLN5 functions as an activator of ceramide synthases. Lipid mass spectrometry, co-immunoprecipitation, differential gel electrophoresis, complementation assays Electrophoresis Low 23160995
2020 CLN5 loss causes impairment of mitochondrial functions; a mitochondria-focused quantitative proteomics approach revealed impaired autophagy machinery and altered mitophagy activation; these mitochondrial defects were confirmed in CLN5 KO cell models and Cln5-/- cerebral cortex and correlated with disease progression. Quantitative proteomics (mitochondria-enriched fractions), immunofluorescence, mitochondrial respiration assays, flow cytometry, patient fibroblast validation Cell death discovery Medium 32257390
2021 CLN5-deficient human neurons (generated by CRISPRi in iPSC-derived cortical neurons) show reduced acidic organelles, reduced lysosomal enzyme activity, and impaired lysosomal movement — the first report of lysosomal trafficking defects in CLN5 disease. CRISPRi knockdown, live microscopy, flow cytometry, lysosomal enzyme activity assays, lysosomal tracking Biomolecules Medium 34680045
2004 The mouse Cln5 gene product is a soluble lysosomal glycoprotein expressed in the developing brain, with prominent expression in cerebellar Purkinje cells, cerebral neurons, and hippocampal cells; expression pattern correlates with CNS regions that degenerate in CLN5 patients. In situ hybridization, immunohistochemistry, in vitro expression in COS-1, HeLa, and neuronal cells Neurobiology of disease Medium 15207259
2004 Cln5-/- mice show loss of vision, accumulation of autofluorescent storage material in CNS and peripheral tissues, prominent loss of GABAergic interneurons in multiple brain areas, and downregulation of myelin structural components; transcript profiling revealed altered expression of genes involved in neurodegeneration and immune/defense responses. Targeted gene deletion (exon 3), electron microscopy, immunohistochemistry, transcript profiling Human molecular genetics High 15459177
2011 Cln5 deficiency in mice leads to early and significant microglial activation (by 3 months), defective myelination in vitro and in developing brain, early alterations in serum lipid profiles, and dysfunctional lipid transport; Cln5 is most highly expressed in microglia. Gene expression analysis, in vitro myelination assays, microglial activation immunostaining, serum lipid profiling Neurobiology of disease Medium 22182690
2019 Loss of Cln5 in mice results in increased neural progenitor cell (NPC) proliferation, reduced NPC migration, and increased neuronal differentiation; neurite outgrowth was compromised in Cln5-/- cortical neurons; impaired interneuron development was linked to increased REST/NRSF binding to the Gad1 locus, reducing GAD67 (rate-limiting enzyme in GABA synthesis) expression. Embryonic brain analysis, BrdU proliferation assay, chromatin immunoprecipitation, primary cortical cultures, EEG Human molecular genetics Medium 31294445
2009 In the Cln5-/- mouse, neuron loss begins in the cortex and only subsequently occurs in thalamic relay nuclei, in marked contrast to other NCL models where neuron loss begins in the thalamus; this is preceded by early and localized glial responses in the thalamocortical system. Stereological analysis, immunohistochemistry, quantitative cell counting across disease progression stages Neurobiology of disease Medium 19385065

Source papers

Stage 0 corpus · 89 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proceedings of the National Academy of Sciences of the United States of America 543 19174516
1998 CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Nature genetics 224 9662406
2002 Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. Human molecular genetics 100 11971870
2002 Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Molecular biology of the cell 90 12134079
2005 A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics 74 16033706
2004 A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging. Human molecular genetics 71 15459177
2012 The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting. Molecular and cellular biology 67 22431521
2009 Novel interactions of CLN5 support molecular networking between Neuronal Ceroid Lipofuscinosis proteins. BMC cell biology 67 19941651
2000 Phenotype-genotype correlation in eight patients with Finnish variant late infantile NCL (CLN5). Neurology 62 10953198
2010 CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology 59 20157158
1996 The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. American journal of human genetics 59 8644710
2007 A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3. Neurobiology of disease 58 17988881
2023 The Batten disease gene product CLN5 is the lysosomal bis(monoacylglycero)phosphate synthase. Science (New York, N.Y.) 55 37708259
2018 Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease. Molecular therapy : the journal of the American Society of Gene Therapy 54 30078766
2004 The mouse ortholog of the neuronal ceroid lipofuscinosis CLN5 gene encodes a soluble lysosomal glycoprotein expressed in the developing brain. Neurobiology of disease 53 15207259
2013 The role of N-glycosylation in folding, trafficking, and functionality of lysosomal protein CLN5. PloS one 51 24058541
2017 Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy. Scientific reports 50 28487519
1999 Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Human mutation 49 10477428
2017 Cln5 is secreted and functions as a glycoside hydrolase in Dictyostelium. Cellular signalling 45 29128403
2012 CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches. Electrophoresis 45 23160995
1996 Efficient construction of a physical map by fiber-FISH of the CLN5 region: refined assignment and long-range contig covering the critical region on 13q22. Genomics 44 8661106
2011 Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism. Neurobiology of disease 43 22182690
2015 Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Molecular genetics and metabolism 41 25934231
2005 A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset. Neurology 41 15728307
2009 Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian sibship. Human mutation 40 19309691
2018 An Alzheimer's Disease-Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation, Consistent with a Retromer Trafficking Defect. Molecular and cellular biology 39 30037983
2010 The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. Human mutation 37 20052765
2009 Progressive thalamocortical neuron loss in Cln5 deficient mice: Distinct effects in Finnish variant late infantile NCL. Neurobiology of disease 37 19385065
2016 Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies. Journal of veterinary internal medicine 35 27203721
2007 Revelation of a novel CLN5 mutation in early juvenile neuronal ceroid lipofuscinosis. Neuropediatrics 35 17607606
2013 Inhibition of storage pathology in prenatal CLN5-deficient sheep neural cultures by lentiviral gene therapy. Neurobiology of disease 34 24269732
2019 Autophagy-lysosome pathway alterations and alpha-synuclein up-regulation in the subtype of neuronal ceroid lipofuscinosis, CLN5 disease. Scientific reports 33 30655561
2014 Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations. Journal of neurology 31 25359263
2020 Proteomic and functional analyses in disease models reveal CLN5 protein involvement in mitochondrial dysfunction. Cell death discovery 28 32257390
2006 Two novel CLN5 mutations in a Portuguese patient with vLINCL: insights into molecular mechanisms of CLN5 deficiency. Molecular genetics and metabolism 28 16814585
2006 Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. Biochimica et biophysica acta 28 16935476
2017 Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses. International journal of molecular sciences 27 28468312
2015 Molecular neuropathology of the synapse in sheep with CLN5 Batten disease. Brain and behavior 27 26664787
2000 CLN-1 and CLN-5, genes for infantile and variant late infantile neuronal ceroid lipofuscinoses, are expressed in the embryonic human brain. The Journal of comparative neurology 27 10992246
2021 Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease. Experimental eye research 26 33930398
2017 Characterisation of early changes in ovine CLN5 and CLN6 Batten disease neural cultures for the rapid screening of therapeutics. Neurobiology of disease 26 28065762
2021 CLN5 and CLN3 function as a complex to regulate endolysosome function. The Biochemical journal 25 34060589
2018 Secretion and function of Cln5 during the early stages of Dictyostelium development. Biochimica et biophysica acta. Molecular cell research 25 30048658
2017 CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein. Experimental cell research 25 28442266
2022 Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. Science advances 24 35427157
2021 A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis. Cellular and molecular life sciences : CMLS 23 33792748
2016 An EEG Investigation of Sleep Homeostasis in Healthy and CLN5 Batten Disease Affected Sheep. The Journal of neuroscience : the official journal of the Society for Neuroscience 23 27488642
2022 KCTD7 mutations impair the trafficking of lysosomal enzymes through CLN5 accumulation to cause neuronal ceroid lipofuscinoses. Science advances 22 35921411
2021 Deficiency of the Lysosomal Protein CLN5 Alters Lysosomal Function and Movement. Biomolecules 20 34680045
2014 Neuronal ceroid lipofuscinosis genes, CLN2, CLN3 and CLN5 are spatially and temporally co-expressed in a developing mouse brain. Experimental and molecular pathology 19 25303899
2015 Proteolytic processing of the neuronal ceroid lipofuscinosis related lysosomal protein CLN5. Experimental cell research 18 26342652
2017 Loss of Cln5 causes altered neurogenesis in a mouse model of a childhood neurodegenerative disorder. Disease models & mechanisms 17 28733362
2021 Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease. Frontiers in cell and developmental biology 16 34291044
2020 Mfsd8 localizes to endocytic compartments and influences the secretion of Cln5 and cathepsin D in Dictyostelium. Cellular signalling 16 32087303
2013 Topology and membrane anchoring of the lysosomal storage disease-related protein CLN5. Human mutation 16 24038957
2001 Studies of homogenous populations: CLN5 and CLN8. Advances in genetics 15 11332769
2019 A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs. Molecular genetics and metabolism 14 31101435
2019 Loss of Cln5 leads to altered Gad1 expression and deficits in interneuron development in mice. Human molecular genetics 14 31294445
2022 Lysosomal Proteomics Links Disturbances in Lipid Homeostasis and Sphingolipid Metabolism to CLN5 Disease. Cells 13 35681535
1999 Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5). Prenatal diagnosis 13 10419622
1994 A variant form of late infantile neuronal ceroid lipofuscinosis (CLN5) is not an allelic form of Batten (Spielmeyer-Vogt-Sjögren, CLN3) disease: exclusion of linkage to the CLN3 region of chromosome 16. Genomics 11 8020979
2022 Lysosomal dysfunction, autophagic defects, and CLN5 accumulation underlie the pathogenesis of KCTD7-mutated neuronal ceroid lipofuscinoses. Autophagy 9 36368077
2024 Mechanisms regulating the intracellular trafficking and release of CLN5 and CTSD. Traffic (Copenhagen, Denmark) 8 38272448
2023 Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease. Frontiers in genetics 8 37614821
2023 Efficacy of dual intracerebroventricular and intravitreal CLN5 gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease. Frontiers in pharmacology 8 37942487
2021 Association of the Recurrent Rare Variant c.415T>C p.Phe139Leu in CLN5 With a Recessively Inherited Macular Dystrophy. JAMA ophthalmology 8 33507209
2020 Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis. Journal of the neurological sciences 8 32302805
2023 Progressive MRI brain volume changes in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinosis. Brain communications 7 36632184
2023 Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease). Developmental neurobiology 7 37246363
2021 Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses. Data in brief 7 34141843
2020 Functional Analysis of a Novel CLN5 Mutation Identified in a Patient With Neuronal Ceroid Lipofuscinosis. Frontiers in genetics 7 32983231
1999 Positional cloning of the CLN5 gene defective in the Finnish variant of the LINCL. Molecular genetics and metabolism 7 10191122
2022 HAGLROS knockdown restrained cell proliferation, migration and invasion and facilitated apoptosis in laryngeal cancer via miR-138-5p/CLN5 axis. Journal of clinical laboratory analysis 6 36347825
2018 Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis. Journal of child neurology 6 30264640
2023 Mechanistic Insights into S-Depalmitolyse Activity of Cln5 Protein Linked to Neurodegeneration and Batten Disease: A QM/MM Study. Journal of the American Chemical Society 5 38055807
2021 Knockdown of CLN5 inhibits the tumorigenic properties of glioblastoma cells via the Akt/mTOR signaling pathway. Oncology letters 5 33777210
2020 CLN5 in heterozygosis may protect against the development of tumors in a VHL patient. Orphanet journal of rare diseases 5 32487141
2019 The Neuronal Ceroid Lipofuscinoses-Linked Loss of Function CLN5 and CLN8 Variants Disrupt Normal Lysosomal Function. Neuromolecular medicine 4 30919163
2012 [Neuronal ceroid lipofuscinosis: diagnostic algorithm and clinical description of the Finnish (CLN5) and Turkish (CLN7) variants late infantile]. Revista de neurologia 4 22532218
1999 Transcript identification on the CLN5 region on chromosome 13q22. Human genetics 3 10480355
2025 CLN5 deficiency impairs glucose uptake and uncovers PHGDH as a potential biomarker in Batten disease. Molecular psychiatry 2 40346285
2023 Characterization of two human induced pluripotent stem cell lines derived from Batten disease patient fibroblasts harbouring CLN5 mutations. Stem cell research 2 38141358
2022 An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum. Frontiers in genetics 2 36437924
2025 Magnetic Resonance Imaging as a Readout of CLN5 Gene Therapy Efficacy in Sheep. Brain and behavior 1 40181626
2024 Drug-refractory epilepsy due to a novel CLN5 mutation: A report of three patients from an Indian family. Seizure 1 39667065
2021 A novel CLN5 mutation in Turkish patient with variant late-onset neuronal ceroid lipofuscinosis and recurrent fractures that causes severe morbidity. Neurocase 1 34678132
2026 Brain-Directed AAV Gene Therapy Rescues a Mouse Model of the CLN5 Form of Neuronal Ceroid Lipofuscinosis Disease and Normalizes a Blood Plasma Biomarker of Neurodegeneration. Human gene therapy 0 41457644
2026 CLN5 disease-causing mutations impact lysosomal biology by affecting intracellular degradation and protein trafficking. Biochimica et biophysica acta. Molecular basis of disease 0 42031177
2025 Genomic insights into autosomal recessive epilepsy: novel pathogenic variants in ITPA and CLN5 identified in consanguineous families. Molecular biology reports 0 41003830