OMIA 001482-9615 : Neuronal ceroid lipofuscinosis, 5 in Canis lupus familiaris

In other species: sheep , cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 256731

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2005

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.

Control: Relatives of affected dogs should be tested. Avoid breeding affected or carrier dogs.

Genetic testing: A test is available.

Breeds: Australian Cattle Dog, Border Collie, Golden Retriever.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
CLN5 ceroid-lipofuscinosis, neuronal 5 Canis lupus familiaris 22 NC_006604.3 (30568572..30575890) CLN5 Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Golden Retriever Neuronal ceroid lipofuscinosis, 5 CLN5 deletion, small (<=20) c.934_935delAG p.E312Vfs*6 2015 25934231 Breed information obtained from Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017
Australian Cattle Dog Border Collie Neuronal ceroid lipofuscinosis, 5 CLN5 nonsense (stop-gain) CanFam3.1 22 g.305746C>T c.619C>T p.Q207* 2005 16033706 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

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.
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 :, 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 :, 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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