OMIA:001482-9615 : Neuronal ceroid lipofuscinosis, 5 in Canis lupus familiaris (dog) |
In other species: taurine cattle , sheep
Categories: Lysosomal storage disease , Nervous system phene
Links to possible relevant human trait(s) and/or gene(s) in OMIM: 256731 (trait) , 608102 (gene)
Links to relevant human diseases in MONDO:
Single-gene trait/disorder: yes
Mode of inheritance: Autosomal recessive
Disease-related: yes
Key variant known: yes
Year key variant first reported: 2005
Cross-species summary: One of several variants of neuronal ceroid lipofuscinosis (NCL) or Batten disease: CLN5; NCL5
Species-specific description: The neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules and early neuronal death. Affected Border collies present at 18-24 months of age. There is a genetic test available.
History: This disorder in dogs was first reported by Taylor and Farrow (1988).
Mapping: Melvile et al. (2005) genotyped animals in their pedigrees with microsatellites in "Likely candidate regions for the disease gene in Border collies based on the conserved synteny between the dog and the human genomes and the positions of NCL genes in human". Linkage analysis rejected chromosomes CFA6 and CFA37, but strongly implicated the region of CFA22 that is orthologous with the region of chromosome HSA13q21.1–q32 that contains CLN5, mutations in which give rise to this disorder in humans.
Molecular basis: Sequencing of the strong comparative positional candidate gene CLN5 (see Mapping section above) revealed to Melville et al. (2005) that the causative mutation in Border Collies is "a nonsense mutation (Q206X) within exon 4" which "should result in a protein product of a size similar to that of some mutations identified in human CLN5 and therefore the Border collie may make a good model for human NCL". CLN5 encodes a soluble lysosomal glycoprotein, the function of which is unknown, but it interacts with the proteins of TPP1 and CLN3 (Vesa et al., 2002). Melville et al. (2005) report the causative variant as c.619C>T or p.Q206X. This curator (T.L.) thinks that the original protein designation (Melville et al. 2005) is incorrect and should actually read p.Q207X, based on the RefSeq entry NM_001011556.1 of the dog CLN 5 transcript. Small deletion in Golden Retrievers: CLN5:c.934_935delAG; p.E312Vfs*6 (Gilliam et al., 2015), who explain that this mutation is "predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids". Kolicheski et al. (2016) reported that affected Australian Cattle Dogs have the same causal mutation as reported by Melville et al. (2005) in Border Collies.
Clinical features: Dogs present at 18-24 months of age with progressive behavioral changes, hyperactivity, dementia, aggression, loss of coordination, ataxia, delayed postural responses, blindness, and slow pupillary light responses (Taylor et al., 1988, Melville et al., 2005). Blind affected dogs have normal retinal structure on fundic and light microscopic examination, but have severe ultrastructural lesions (Taylor et al., 1988). Changes observed by MRI include slightly dilated cerebral sulci and cerebellar fissures, and left ventricular enlargement (Koie et al., 2004).
Pathology: There is widespread accumulation of autofluorescent storage granules in the cerebrum, cerebellum, and spinal cord. In the cerebellum there is Purkinje cell depletion, and those remaining contain eosinophilic, autofluorescent granules. Storage also occurs in the ganglion cells of the retina, peribronchial phagocytes, Kupffer cells, macrophages in the spleen, renal tubular epithelium, thyroid epithelial cells, enteric ganglia and submucosal plexus cells (Taylor et al., 1988).
Prevalence: The frequency of the c.619C>T allele is estimated at 3.5% in the Border collie population of Australia (Melville et al., 2005). Mizukami et al. (2016) reported the frequency of the c.619C>T allele as 0.035 in 500 Border collies in Japan. Villani et al. (2019) reported the c.619C>T variant to be homozygous in an affected mixed-breed dog of unknown parentage. They also reported a 87kb haplotype including the variant that is shared by this affected dog and the breeds in which this variant has been previously reported. Villani et al. (2019) concluded "that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed."
Control: Relatives of affected dogs should be tested. Avoid breeding affected dogs. If a carrier dog is bred with a dog that is DNA tested to not have the disease causing mutation, then all offspring need to be DNA tested to reduce the risk of future carrier by carrier matings.
Genetic testing: A test is available.
Breeds:
Australian Cattle Dog (Dog) (VBO_0200088),
Border Collie (Dog) (VBO_0200193),
Golden Retriever (Dog) (VBO_0200610).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).
Associated gene:
Symbol | Description | Species | Chr | Location | OMIA gene details page | Other Links |
---|---|---|---|---|---|---|
CLN5 | ceroid-lipofuscinosis, neuronal 5 | Canis lupus familiaris | 22 | NC_051826.1 (30880658..30887978) | CLN5 | Homologene, Ensembl , NCBI gene |
Variants
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
OMIA Variant ID | Breed(s) | Variant Phenotype | Gene | Allele | Type of Variant | Source of Genetic Variant | Reference Sequence | Chr. | g. or m. | c. or n. | p. | Verbal Description | EVA ID | Year Published | PubMed ID(s) | Acknowledgements |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
279 | Australian Cattle Dog (Dog) Border Collie (Dog) | Neuronal ceroid lipofuscinosis, 5 | CLN5 | nonsense (stop-gain) | Naturally occurring variant | CanFam3.1 | 22 | g.30574637C>T | c.619C>T | p.(Q207*) | rs1152388418 | 2005 | 16033706 | Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool 30 Dec 2020: g. coordinate corrected, with thanks to Angelica K Kallenberg | ||
541 | Golden Retriever (Dog) | Neuronal ceroid lipofuscinosis, 5 | CLN5 | deletion, small (<=20) | Naturally occurring variant | CanFam3.1 | 22 | g.30574953_30574954del | c.935_936del | p.(E312Vfs*6) | NM_001011556.1; NP_001011556.1,published as CLN5:c.934_935delAG; coordinates in the table have been updated to a recent reference genome and / or transcript | 2015 | 25934231 | Breed information obtained from Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017; Genomic coordinates in CanFam3.1 provided by Zoe Shmidt and Robert Kuhn. |
Cite this entry
Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:001482-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70
References
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2023 | Cocostîrc, V., Paștiu, A.I., Pusta, D.L. : |
An overview of canine inherited neurological disorders with known causal variants. Animals (Basel) 13:3568, 2023. Pubmed reference: 38003185. DOI: 10.3390/ani13223568. | |
2022 | Meiman, E.J., Kick, G.R., Jensen, C.A., Coates, J.R., Katz, M.L. : |
Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis. Dev Neurobiol 82:326-344, 2022. Pubmed reference: 35427439. DOI: 10.1002/dneu.22878. | |
2021 | Basak, I., Wicky, H.E., McDonald, K.O., Xu, J.B., Palmer, J.E., Best, H.L., Lefrancois, S., Lee, S.Y., Schoderboeck, L., Hughes, S.M. : |
A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis. Cell Mol Life Sci 78:4735-63, 2021. Pubmed reference: 33792748. DOI: 10.1007/s00018-021-03813-x. | |
Cerda-Gonzalez, S., Packer, R.A., Garosi, L., Lowrie, M., Mandigers, P.J.J., O'Brien, D.P., Volk, H.A. : | |
International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification. J Vet Intern Med 35:1218-1230, 2021. Pubmed reference: 33769611. DOI: 10.1111/jvim.16108. | |
Kick, G.R., Meiman, E.J., Sabol, J.C., Whiting, R.E.H., Ota-Kuroki, J., Castaner, L.J., Jensen, C.A., Katz, M.L. : | |
Visual system pathology in a canine model of CLN5 neuronal ceroid lipofuscinosis. Exp Eye Res 210:108686, 2021. Pubmed reference: 34216614. DOI: 10.1016/j.exer.2021.108686. | |
Soh, P.X.Y., Hsu, W.T., Khatkar, M.S., Williamson, P. : | |
Evaluation of genetic diversity and management of disease in Border Collie dogs. Sci Rep 11:6243, 2021. Pubmed reference: 33737533. DOI: 10.1038/s41598-021-85262-x. | |
2020 | Story, B.D., Miller, M.E., Bradbury, A.M., Million, E.D., Duan, D., Taghian, T., Faissler, D., Fernau, D., Beecy, S.J., Gray-Edwards, H.L. : |
Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80, 2020. Pubmed reference: 32219101. DOI: 10.3389/fvets.2020.00080. | |
2019 | Villani, N.A., Bullock, G., Michaels, J.R., Yamato, O., O'Brien, D.P., Mhlanga-Mutangadura, T., Johnson, G.S., Katz, M.L. : |
A mixed breed dog with neuronal ceroid lipofuscinosis is homozygous for a CLN5 nonsense mutation previously identified in Border Collies and Australian Cattle Dogs. Mol Genet Metab 127:107-115, 2019. Pubmed reference: 31101435. DOI: 10.1016/j.ymgme.2019.04.003. | |
2017 | Katz, M.L., Rustad, E., Robinson, G.O., Whiting, R.E.H., Student, J.T., Coates, J.R., Narfstrom, K. : |
Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions. Neurobiol Dis 108:277-87, 2017. Pubmed reference: 28860089. DOI: 10.1016/j.nbd.2017.08.017. | |
2016 | Kolicheski, A., Johnson, G.S., O'Brien, D.P., Mhlanga-Mutangadura, T., Gilliam, D., Guo, J., Anderson-Sieg, T.D., Schnabel, R.D., Taylor, J.F., Lebowitz, A., Swanson, B., Hicks, D., Niman, Z.E., Wininger, F.A., Carpentier, M.C., Katz, M.L. : |
Australian Cattle dogs with neuronal ceroid lipofuscinosis are homozygous for a CLN5 nonsense mutation previously identified in Border Collies. J Vet Intern Med 30:1149-58, 2016. Pubmed reference: 27203721. DOI: 10.1111/jvim.13971. | |
Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. : | |
Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004. | |
2015 | Gilliam, D., Kolicheski, A., Johnson, G.S., Mhlanga-Mutangadura, T., Taylor, J.F., Schnabel, R.D., Katz, M.L. : |
Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Mol Genet Metab 115:101-9, 2015. Pubmed reference: 25934231. DOI: 10.1016/j.ymgme.2015.04.001. | |
2013 | Bond, M., Holthaus, S.M., Tammen, I., Tear, G., Russell, C. : |
Use of model organisms for the study of neuronal ceroid lipofuscinosis. Biochim Biophys Acta 1832:1842-65, 2013. Pubmed reference: 23338040. DOI: 10.1016/j.bbadis.2013.01.009. | |
2012 | Mizukami, K., Kawamichi, T., Koie, H., Tamura, S., Matsunaga, S., Imamoto, S., Saito, M., Hasegawa, D., Matsuki, N., Tamahara, S., Sato, S., Yabuki, A., Chang, H.S., Yamato, O. : |
Neuronal ceroid lipofuscinosis in Border Collie dogs in Japan: clinical and molecular epidemiological study (2000-2011). ScientificWorldJournal 2012:383174, 2012. Pubmed reference: 22919312. DOI: 10.1100/2012/383174. | |
2011 | Mizukami, K., Chang, H.S., Yabuki, A., Kawamichi, T., Kawahara, N., Hayashi, D., Hossain, M.A., Rahman, M.M., Uddin, M.M., Yamato, O. : |
Novel rapid genotyping assays for neuronal ceroid lipofuscinosis in Border Collie dogs and high frequency of the mutant allele in Japan. J Vet Diagn Invest 23:1131-9, 2011. Pubmed reference: 22362793. DOI: 10.1177/1040638711425590. | |
2005 | Melville, SA., Wilson, CL., Chiang, CS., Studdert, VP., Lingaas, F., Wilton, AN. : |
A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics 86:287-94, 2005. Pubmed reference: 16033706. DOI: 10.1016/j.ygeno.2005.06.005. | |
2004 | Koie, H., Shibuya, H., Sato, T., Sato, A., Nawa, K., Nawa, Y., Kitagawa, M., Sakai, M., Takahashi, T., Yamaya, Y., Yamato, O., Watari, T., Tokuriki, M. : |
Magnetic resonance imaging of neuronal ceroid lipofuscinosis in a border collie. J Vet Med Sci 66:1453-6, 2004. Pubmed reference: 15585966. DOI: 10.1292/jvms.66.1453. | |
2002 | Vesa, J., Chin, M.H., Oelgeschläger, K., Isosomppi, J., DellAngelica, E.C., Jalanko, A., Peltonen, L. : |
Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. Mol Biol Cell 13:2410-20, 2002. Pubmed reference: 12134079. DOI: 10.1091/mbc.E02-01-0031. | |
1999 | Franks, J.N., Dewey, C.W., Walker, M.A., Storts, R.W. : |
Computed tomographic findings of ceroid lipofuscinosis in a dog J Am Anim Hosp Assoc 35:430-5, 1999. Pubmed reference: 10493420. DOI: 10.5326/15473317-35-5-430. | |
1992 | Taylor, R.M., Farrow, B.R.H. : |
Ceroid Lipofuscinosis in the Border Collie Dog - Retinal Lesions in an Animal Model of Juvenile Batten Disease American Journal of Medical Genetics 42:622-627, 1992. Pubmed reference: 1319117. DOI: 10.1002/ajmg.1320420438. | |
1991 | Studdert, V.P., Mitten, R.W. : |
Clinical Features of Ceroid Lipofuscinosis in Border Collie Dogs Aust Vet J 68:137-40, 1991. Pubmed reference: 2069541. DOI: 10.1111/j.1751-0813.1991.tb03156.x. | |
1988 | Taylor, R.M., Farrow, B.R. : |
Ceroid-lipofuscinosis in border collie dogs. Acta Neuropathol 75:627-31, 1988. Pubmed reference: 3376765. DOI: 10.1007/BF00686209. |
Edit History
- Created by Frank Nicholas on 26 Oct 2010
- Changed by Vicki Meyers-Wallen on 18 Sep 2011
- Changed by Frank Nicholas on 12 Dec 2011
- Changed by Frank Nicholas on 22 Oct 2012
- Changed by Tosso Leeb on 28 May 2013
- Changed by Frank Nicholas on 20 Aug 2013
- Changed by Frank Nicholas on 02 May 2015
- Changed by Frank Nicholas on 26 May 2016
- Changed by Frank Nicholas on 18 Oct 2016
- Changed by Frank Nicholas on 22 May 2019
- Changed by Imke Tammen2 on 08 Aug 2021
- Changed by Imke Tammen2 on 13 Nov 2023