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Gene Review

CLN5  -  ceroid-lipofuscinosis, neuronal 5

Homo sapiens

Synonyms: Ceroid-lipofuscinosis neuronal protein 5, Protein CLN5
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Disease relevance of CLN5


Psychiatry related information on CLN5

  • Sleep disorders are common in NCL patients [6].
  • The high dolichol values in NCL, Alzheimer's disease, and senescence appears to be related to the increase of lipofuscin in brain [7].
  • Clinical symptomatology differs from the classical childhood NCL forms in that ocular symptoms are absent while changes of behavior, dementia and seizures dominate the clinical picture [8].

High impact information on CLN5

  • Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype (CLN8) [9].
  • Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL [9].
  • All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death [10].
  • The infantile subtype of NCL (INCL), linked to chromosome 1p32, is characterized by early visual loss and rapidly progressing mental deterioration, resulting in a flat electroencephalogram by 3 years of age; death occurs at 8 to 11 years, and characteristic storage bodies are found in brain and other tissues at autopsy [11].
  • These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease [12].

Chemical compound and disease context of CLN5

  • Deficiency in a recently characterized lysosomal enzyme, palmitoyl-protein thioesterase (PPT), leads to a severe neurodegenerative disorder of children, infantile neuronal ceroid lipofuscinosis (NCL) [13].
  • We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate [14].
  • In the current study, using subtraction cloning for genes that are differentially expressed in metastasis, the authors isolated a clone encoding ceroid lipofuscinosis, neuronal 2 (CLN2), which is a lysosomal serine protease defective in neuronal ceroid lipofuscinosis (NCL) [15].
  • Therefore, the normal laboratory diets of NCL dogs were supplemented with carnitine, fish oil and corn oil and the disease progression was compared with that of an untreated litter mate [16].
  • Adult Neuronal Ceroid Lipofuscinosis (Adult NCL), also known as Kuf's Disease, is a rare progressive encephalopathic disease that results in dementia [17].

Biological context of CLN5

  • Both intracellular targeting and posttranslational glycosylation of the polypeptides carrying human disease mutations were similar to wild-type CLN5 [18].
  • 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 [19].
  • Using the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families [20].
  • Recent promising molecular genetic studies have, however, revealed the gene for infantile neuronal ceroid-lipofuscinosis, CLN1, on chromosome 1p32; the gene for juvenile neuronal ceroid-lipofuscinosis, CLN3, on chromosome 16p12.1-11.2; and the gene for a Finnish variant of late-infantile neuronal ceroid-lipofuscinosis, CLN5, on chromosome 13q31-32 [21].
  • DNA analysis showed that the fetus had inherited the major mutation, a 2 bp deletion of the CLN5 gene from the mother, and the same paternal (and maternal) haplotypes for COLAC1 and AC224 as the affected daughter [22].

Anatomical context of CLN5

  • The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown [23].
  • The CLN3 and CLN5 genes show ubiquitous expression patterns and are targeted to lysosomes in vitro, but the observed synaptosomal localization of the CLN3 protein in neurons would suggest some cell specificity in targeting and function of these proteins [1].
  • As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies [24].
  • The composition of inclusion bodies varies in different forms of the NCL [2].
  • Electron microscopy of a chorionic villus sample (CVS) at the 11th week of gestation did not reveal inclusions characteristic for NCL [22].

Associations of CLN5 with chemical compounds

  • Mutations in the gene encoding a lysosomal enzyme, palmitoyl protein thioesterase (PPT), cause infantile NCL (locus CLN1 on chromosome 1p32) or Haltia-Santavuori disease [25].
  • Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C>T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR [26].
  • The same-sized glycosylated polypeptides were also observed in the media, suggesting that the 60 kDa glycosylated CLN5 polypeptide represents a soluble lysosomal glycoprotein, not an integral transmembrane protein as predicted earlier [27].
  • Furthermore, HR MAS 1H MR spectra facilitated refined detection of neuronal metabolites, including GABA, and composition of lipids in the autopsy brain tissue of NCL patients [28].
  • Carnitine and polyunsaturated fatty acids have been reported to be reduced in NCL English Setters [16].

Other interactions of CLN5

  • The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children [29].
  • Genomic and proteomic approaches have presently identified eight different forms of NCL (namely, CLN1 through CLN8) based on mutations in specific genes [2].
  • Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL) [30].
  • These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes ( [30].
  • Genetic variants such as CLN6 might therefore cause a significant portion of childhood NCL in the Portuguese population.The relative frequency of classical childhood forms of NCL in the Portuguese population is reported and contributes to the knowledge of genetic epidemiology of these world-widely distributed disorders [31].

Analytical, diagnostic and therapeutic context of CLN5

  • Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5) [22].
  • This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed [24].
  • Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice [32].
  • Although the clinical phenotype of these NCL subtypes differs in the age of onset, average life span and EEG findings, the major component of material accumulating in patients' lysosomes is subunit c of mitochondrial ATPase in both these diseases [1].
  • Confocal immunofluorescence microscopy showed that wild-type CLN5 is predominantly targeted to lysosomes and immunoprecipitation analysis recognized a 60 kDa polypeptide [27].


  1. Mutated genes in juvenile and variant late infantile neuronal ceroid lipofuscinoses encode lysosomal proteins. Vesa, J., Peltonen, L. Curr. Mol. Med. (2002) [Pubmed]
  2. Biochemistry of neuronal ceroid lipofuscinoses. Junaid, M.A., Pullarkat, R.K. Adv. Genet. (2001) [Pubmed]
  3. Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. Mitchell, W.A., Wheeler, R.B., Sharp, J.D., Bate, S.L., Gardiner, R.M., Ranta, U.S., Lonka, L., Williams, R.E., Lehesjoki, A.E., Mole, S.E. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  4. 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. Klockars, T., Savukoski, M., Isosomppi, J., Laan, M., Järvelä, I., Petrukhin, K., Palotie, A., Peltonen, L. Genomics (1996) [Pubmed]
  5. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Awano, T., Katz, M.L., O'brien, D.P., Sohar, I., Lobel, P., Coates, J.R., Khan, S., Johnson, G.C., Giger, U., Johnson, G.S. Mol. Genet. Metab. (2006) [Pubmed]
  6. Circadian rhythm studies in neuronal ceroid-lipofuscinosis (NCL). Heikkilä, E., Hàtònen, T.H., Telakivi, T., Laakso, M.L., Heiskala, H., Salmi, T., Alila, A., Santavuori, P. Am. J. Med. Genet. (1995) [Pubmed]
  7. High levels of brain dolichols in neuronal ceroid-lipofuscinosis and senescence. Ng Ying Kin, N.M., Palo, J., Haltia, M., Wolfe, L.S. J. Neurochem. (1983) [Pubmed]
  8. Adult neuronal ceroid-lipofuscinosis. Goebel, H.H., Braak, H. Clin. Neuropathol. (1989) [Pubmed]
  9. The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8. Ranta, S., Zhang, Y., Ross, B., Lonka, L., Takkunen, E., Messer, A., Sharp, J., Wheeler, R., Kusumi, K., Mole, S., Liu, W., Soares, M.B., Bonaldo, M.F., Hirvasniemi, A., de la Chapelle, A., Gilliam, T.C., Lehesjoki, A.E. Nat. Genet. (1999) [Pubmed]
  10. CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. Savukoski, M., Klockars, T., Holmberg, V., Santavuori, P., Lander, E.S., Peltonen, L. Nat. Genet. (1998) [Pubmed]
  11. Mutations in the palmitoyl protein thioesterase gene causing infantile neuronal ceroid lipofuscinosis. Vesa, J., Hellsten, E., Verkruyse, L.A., Camp, L.A., Rapola, J., Santavuori, P., Hofmann, S.L., Peltonen, L. Nature (1995) [Pubmed]
  12. Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6. Poët, M., Kornak, U., Schweizer, M., Zdebik, A.A., Scheel, O., Hoelter, S., Wurst, W., Schmitt, A., Fuhrmann, J.C., Planells-Cases, R., Mole, S.E., Hübner, C.A., Jentsch, T.J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Biochemical analysis of mutations in palmitoyl-protein thioesterase causing infantile and late-onset forms of neuronal ceroid lipofuscinosis. Das, A.K., Lu, J.Y., Hofmann, S.L. Hum. Mol. Genet. (2001) [Pubmed]
  14. Increased brain lysosomal pepstatin-insensitive proteinase activity in patients with neurodegenerative diseases. Junaid, M.A., Pullarkat, R.K. Neurosci. Lett. (1999) [Pubmed]
  15. Overexpression in colorectal carcinoma of two lysosomal enzymes, CLN2 and CLN1, involved in neuronal ceroid lipofuscinosis. Tsukamoto, T., Iida, J., Dobashi, Y., Furukawa, T., Konishi, F. Cancer (2006) [Pubmed]
  16. Assessment of dietary therapies in a canine model of Batten disease. Siakotos, A.N., Hutchins, G.D., Farlow, M.R., Katz, M.L. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  17. The neuropsychology of Kuf's Disease: a case of atypical early onset dementia. Hinkebein, J.H., Callahan, C.D. Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists. (1997) [Pubmed]
  18. Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Vesa, J., Chin, M.H., Oelgeschläger, K., Isosomppi, J., DellAngelica, E.C., Jalanko, A., Peltonen, L. Mol. Biol. Cell (2002) [Pubmed]
  19. 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]
  20. Linkage analysis of late-infantile neuronal ceroid-lipofuscinosis. Sharp, J., Savukoski, M., Wheeler, R.B., Harris, J., Järvelä, I., Peltonen, L., Gardiner, M., Williams, R. Am. J. Med. Genet. (1995) [Pubmed]
  21. The neuronal ceroid-lipofuscinoses. Goebel, H.H. J. Child Neurol. (1995) [Pubmed]
  22. Prenatal diagnosis of variant late infantile neuronal ceroid lipofuscinosis (vLINCL[Finnish]; CLN5). Rapola, J., Lähdetie, J., Isosomppi, J., Helminen, P., Penttinen, M., Järvelä, I. Prenat. Diagn. (1999) [Pubmed]
  23. 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]
  24. Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. Houweling, P.J., Cavanagh, J.A., Palmer, D.N., Frugier, T., Mitchell, N.L., Windsor, P.A., Raadsma, H.W., Tammen, I. Biochim. Biophys. Acta (2006) [Pubmed]
  25. Molecular genetics of the neuronal ceroid lipofuscinoses. Mole, S., Gardiner, M. Epilepsia (1999) [Pubmed]
  26. A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA. Tammen, I., Houweling, P.J., Frugier, T., Mitchell, N.L., Kay, G.W., Cavanagh, J.A., Cook, R.W., Raadsma, H.W., Palmer, D.N. Biochim. Biophys. Acta (2006) [Pubmed]
  27. Lysosomal localization of the neuronal ceroid lipofuscinosis CLN5 protein. Isosomppi, J., Vesa, J., Jalanko, A., Peltonen, L. Hum. Mol. Genet. (2002) [Pubmed]
  28. 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]
  29. The genetic spectrum of human neuronal ceroid-lipofuscinoses. Mole, S.E. Brain Pathol. (2004) [Pubmed]
  30. Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. Wisniewski, K.E., Zhong, N., Philippart, M. Neurology (2001) [Pubmed]
  31. Clinicopathological and molecular characterization of neuronal ceroid lipofuscinosis in the Portuguese population. Teixeira, C., Guimarães, A., Bessa, C., Ferreira, M.J., Lopes, L., Pinto, E., Pinto, R., Boustany, R.M., Sá Miranda, M.C., Ribeiro, M.G. J. Neurol. (2003) [Pubmed]
  32. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Mole, S.E., Williams, R.E., Goebel, H.H. Neurogenetics (2005) [Pubmed]
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