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Gene Review

CLN3  -  ceroid-lipofuscinosis, neuronal 3

Homo sapiens

Synonyms: BTS, Batten disease protein, Battenin, JNCL, Protein CLN3
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Disease relevance of CLN3


Psychiatry related information on CLN3


High impact information on CLN3


Chemical compound and disease context of CLN3

  • PPT1 deficiency in humans causes a neurodegenerative disorder, infantile neuronal ceroid lipofuscinosis (also known as infantile Batten disease) [15].
  • Mutations in the CLN1 gene encoding palmitoyl-protein thioesterase (PPT) underlie the recessive neurodegenerative disorder, infantile Batten disease, or infantile neuronal ceroid lipofuscinosis (INCL) [16].
  • The decreased activity of GAD65 and increased levels of glutamate may have a causative role in astrocytic hypertrophy evident in cln3-knockout mice, and in altered expression of genes involved in the synthesis and utilization of glutamate that underlie a shift from synthesis to utilization of glutamate [17].
  • BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia [18].
  • To illustrate our methods, we applied them to two groups of data sets, one is cystic fibrosis data collected from several European populations, and the other is data on several genetic diseases (diastrophic dysplasia, progressive myoclonus epilepsy, congenital chloride diarrhea, and Batten disease) all collected from the Finnish population [19].

Biological context of CLN3

  • 1. The D16S298/D16S299 haplotype "5/4" is highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes (chi 2 = 117, df = 1, P < .001) [20].
  • Examination of the haplotypes suggests that the CLN3 locus can be narrowed to the region immediately surrounding these markers in 16p12 [20].
  • The gene loci for the juvenile (CLN3) and infantile (CLN1) types have been mapped to human chromosomes 16p and 1p, respectively, by linkage analysis [21].
  • We find significant linkage disequilibrium between CLN3 and the dinucleotide repeat marker loci D16S288 (chi 2(7) = 46.5, P < .005), D16S298 (chi 2(6) = 36.6, P < .005), and D16S299 (chi 2(7) = 73.8, P < .005), and also a novel RFLP marker at the D16S272 locus (chi 2(1) = 5.7, P = .02) [20].
  • Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis [22].

Anatomical context of CLN3


Associations of CLN3 with chemical compounds


Regulatory relationships of CLN3

  • Ex vivo spectra from CLN1 autopsy brain tissue (n = 9) significantly differed from those of the control (n = 9) and CLN3 (n = 5) groups, although no differences were found between the CLN3 and the control groups [29].
  • CLN3 protein regulates lysosomal pH and alters intracellular processing of Alzheimer's amyloid-beta protein precursor and cathepsin D in human cells [7].
  • CLN-3 protein is expressed in the pancreatic somatostatin-secreting delta cells [30].

Other interactions of CLN3

  • The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children [31].
  • The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology [32].
  • The gene locus causing the classical late infantile form (CLN2) has not yet been mapped but has been excluded from both CLN1 and CLN3 loci (8) [33].
  • They result from mutations on genes CLN1, CLN2, and CLN3, respectively [34].
  • Subunit c of mitochondrial ATP synthase specifically accumulates in most of them, including the juvenile CLN3 form and a sheep form orthologous to CLN6 [35].

Analytical, diagnostic and therapeutic context of CLN3

  • Using oligonucleotide arrays we identified reproducible changes in gene expression in the brains of both 10-week-old Cln1- and Cln3-knockout mice as compared to wild-type controls, and confirmed changes in levels of several of the cognate proteins by immunoblotting [36].
  • Pulse-chase labelling and immunoprecipitation of the two mutant proteins in COS-1-cells indicated that 461-677del is synthesized as an approximately 24 kDa truncated polypeptide, whereas the maturation of E295K [corrected] resembles that of the wild-type CLN3 polypeptide [37].
  • In this study, we have confirmed the lysosomal localization of the CLN3 protein by immunoelectron microscopy by co-localizing it with soluble and membrane-associated lysosomal proteins [37].
  • In the present study, we investigated the pathways and mechanisms of CLN3 sorting using biochemical binding assays and immunofluorescence methods [6].
  • Different bands, some with different subcellular distributions, were detected by antisera against different regions of CLN3 on Western blots of sheep tissues [35].


  1. A murine model for juvenile NCL: gene targeting of mouse Cln3. Greene, N.D., Bernard, D.L., Taschner, P.E., Lake, B.D., de Vos, N., Breuning, M.H., Gardiner, R.M., Mole, S.E., Nussbaum, R.L., Mitchison, H.M. Mol. Genet. Metab. (1999) [Pubmed]
  2. Batten's disease: clues to neuronal protein catabolism in lysosomes. Dawson, G., Cho, S. J. Neurosci. Res. (2000) [Pubmed]
  3. Novel CLN3 mutation predicted to cause complete loss of protein function does not modify the classical JNCL phenotype. Kwon, J.M., Rothberg, P.G., Leman, A.R., Weimer, J.M., Mink, J.W., Pearce, D.A. Neurosci. Lett. (2005) [Pubmed]
  4. The CLN3 gene is a novel molecular target for cancer drug discovery. Rylova, S.N., Amalfitano, A., Persaud-Sawin, D.A., Guo, W.X., Chang, J., Jansen, P.J., Proia, A.D., Boustany, R.M. Cancer Res. (2002) [Pubmed]
  5. Neuronal ceroid lipofuscinoses: research update. Wisniewski, K.E., Kida, E., Connell, F., Zhong, N. Neurol. Sci. (2000) [Pubmed]
  6. AP-1 and AP-3 facilitate lysosomal targeting of Batten disease protein CLN3 via its dileucine motif. Kyttälä, A., Yliannala, K., Schu, P., Jalanko, A., Luzio, J.P. J. Biol. Chem. (2005) [Pubmed]
  7. CLN3 protein regulates lysosomal pH and alters intracellular processing of Alzheimer's amyloid-beta protein precursor and cathepsin D in human cells. Golabek, A.A., Kida, E., Walus, M., Kaczmarski, W., Michalewski, M., Wisniewski, K.E. Mol. Genet. Metab. (2000) [Pubmed]
  8. Expression of cln3 in human NT2 neuronal precursor cells and neonatal rat brain. Pane, M.A., Puranam, K.L., Boustany, R.M. Pediatr. Res. (1999) [Pubmed]
  9. Linkage analysis in juvenile neuronal ceroid lipofuscinosis. Haines, J.L., Yan, W.L., Boustany, R.M., Jewell, A., Julier, C., Breakefield, X.O., Gusella, J.F. Am. J. Med. Genet. (1992) [Pubmed]
  10. Action of BTN1, the yeast orthologue of the gene mutated in Batten disease. Pearce, D.A., Ferea, T., Nosel, S.A., Das, B., Sherman, F. Nat. Genet. (1999) [Pubmed]
  11. Immunoreactivity of ceroid lipofuscin storage pigment in Batten disease with monoclonal antibodies to the amyloid beta-protein. Wisniewski, K.E., Maslinska, D. N. Engl. J. Med. (1989) [Pubmed]
  12. Identification of retinoyl complexes as the autofluorescent component of the neuronal storage material in Batten disease. Wolfe, L.S., Kin, N.M., Baker, R.R., Carpenter, S., Andermann, F. Science (1977) [Pubmed]
  13. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Green, R.H., Brightling, C.E., McKenna, S., Hargadon, B., Parker, D., Bradding, P., Wardlaw, A.J., Pavord, I.D. Lancet (2002) [Pubmed]
  14. Integrating maps of chromosome 16. Mulley, J.C., Sutherland, G.R. Curr. Opin. Genet. Dev. (1993) [Pubmed]
  15. Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice. Gupta, P., Soyombo, A.A., Atashband, A., Wisniewski, K.E., Shelton, J.M., Richardson, J.A., Hammer, R.E., Hofmann, S.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  16. Positional candidate gene cloning of CLN1. Hofmann, S.L., Das, A.K., Lu, J.Y., Soyombo, A.A. Adv. Genet. (2001) [Pubmed]
  17. An autoantibody inhibitory to glutamic acid decarboxylase in the neurodegenerative disorder Batten disease. Chattopadhyay, S., Ito, M., Cooper, J.D., Brooks, A.I., Curran, T.M., Powers, J.M., Pearce, D.A. Hum. Mol. Genet. (2002) [Pubmed]
  18. The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates. Hansard, M.J., Smith, L.A., Jackson, M.J., Cheetham, S.C., Jenner, P. Mov. Disord. (2004) [Pubmed]
  19. Estimating the age of mutant disease alleles based on linkage disequilibrium. Guo, S.W., Xiong, M. Hum. Hered. (1997) [Pubmed]
  20. Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p 12.1. Lerner, T.J., Boustany, R.M., MacCormack, K., Gleitsman, J., Schlumpf, K., Breakefield, X.O., Gusella, J.F., Haines, J.L. Am. J. Hum. Genet. (1994) [Pubmed]
  21. Genetic heterogeneity in neuronal ceroid lipofuscinosis (NCL): evidence that the late-infantile subtype (Jansky-Bielschowsky disease; CLN2) is not an allelic form of the juvenile or infantile subtypes. Williams, R., Vesa, J., Järvelä, I., McKay, T., Mitchison, H., Hellsten, E., Thompson, A., Callen, D., Sutherland, G., Luna-Battadano, D. Am. J. Hum. Genet. (1993) [Pubmed]
  22. Flupirtine blocks apoptosis in batten patient lymphoblasts and in human postmitotic CLN3- and CLN2-deficient neurons. Dhar, S., Bitting, R.L., Rylova, S.N., Jansen, P.J., Lockhart, E., Koeberl, D.D., Amalfitano, A., Boustany, R.M. Ann. Neurol. (2002) [Pubmed]
  23. Tissue expression and subcellular localization of CLN3, the Batten disease protein. Margraf, L.R., Boriack, R.L., Routheut, A.A., Cuppen, I., Alhilali, L., Bennett, C.J., Bennett, M.J. Mol. Genet. Metab. (1999) [Pubmed]
  24. The neuronal ceroid-lipofuscinoses (Batten disease): a new class of lysosomal storage diseases. Bennett, M.J., Hofmann, S.L. J. Inherit. Metab. Dis. (1999) [Pubmed]
  25. Mitochondrial abnormalities in CLN2 and CLN3 forms of Batten disease. Dawson, G., Kilkus, J., Siakotos, A.N., Singh, I. Mol. Chem. Neuropathol. (1996) [Pubmed]
  26. A role in vacuolar arginine transport for yeast Btn1p and for human CLN3, the protein defective in Batten disease. Kim, Y., Ramirez-Montealegre, D., Pearce, D.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  27. Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis. Wisniewski, K.E., Zhong, N., Kaczmarski, W., Kaczmarski, A., Kida, E., Brown, W.T., Schwarz, K.O., Lazzarini, A.M., Rubin, A.J., Stenroos, E.S., Johnson, W.G., Wisniewski, T.M. Ann. Neurol. (1998) [Pubmed]
  28. A galactosylceramide binding domain is involved in trafficking of CLN3 from Golgi to rafts via recycling endosomes. Persaud-Sawin, D.A., McNamara, J.O., Rylova, S., Vandongen, A., Boustany, R.M. Pediatr. Res. (2004) [Pubmed]
  29. High-resolution magic angle spinning and 1H magnetic resonance spectroscopy reveal significantly altered neuronal metabolite profiles in CLN1 but not in CLN3. Sitter, B., Autti, T., Tyynelä, J., Sonnewald, U., Bathen, T.F., Puranen, J., Santavuori, P., Haltia, M.J., Paetau, A., Polvikoski, T., Gribbestad, I.S., Häkkinen, A.M. J. Neurosci. Res. (2004) [Pubmed]
  30. CLN-3 protein is expressed in the pancreatic somatostatin-secreting delta cells. Boriack, R.L., Bennett, M.J. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  31. The genetic spectrum of human neuronal ceroid-lipofuscinoses. Mole, S.E. Brain Pathol. (2004) [Pubmed]
  32. Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Wisniewski, K.E., Zhong, N., Philippart, M. Neurology (2001) [Pubmed]
  33. 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. Williams, R., Santavuori, P., Peltonen, L., Gardiner, R.M., Järvelä, I. Genomics (1994) [Pubmed]
  34. Molecular diagnosis of and carrier screening for the neuronal ceroid lipofuscinoses. Zhong, N.A., Wisniewski, K.E., Ju, W., Moroziewicz, D.N., Jurkiewicz, A., McLendon, L., Jenkins, E.C., Brown, W.T. Genet. Test. (2000) [Pubmed]
  35. Splicing variants in sheep CLN3, the gene underlying juvenile neuronal ceroid lipofuscinosis. Oswald, M.J., Palmer, D.N., Damak, S. Mol. Genet. Metab. (1999) [Pubmed]
  36. Early changes in gene expression in two models of Batten disease. Elshatory, Y., Brooks, A.I., Chattopadhyay, S., Curran, T.M., Gupta, P., Ramalingam, V., Hofmann, S.L., Pearce, D.A. FEBS Lett. (2003) [Pubmed]
  37. Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). Järvelä, I., Lehtovirta, M., Tikkanen, R., Kyttälä, A., Jalanko, A. Hum. Mol. Genet. (1999) [Pubmed]
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