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

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 256731 (trait) , 608102 (gene)

Links to MONDO diseases:

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: 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.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

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. For breeds in which a likely causal variant has been documented, see the variant table below

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

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

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 Inferred EVA rsID 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 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.

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.
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 Journal of the American Animal Hospital Association 35:430-435, 1999. Pubmed reference: 10493420.
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 Australian Veterinary Journal 68:137-140, 1991. Pubmed reference: 2069541.
1988 Taylor, R.M., Farrow, B.R. :
Ceroid-lipofuscinosis in border collie dogs. Acta Neuropathol 75:627-31, 1988. Pubmed reference: 3376765.

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