OMIA:001506-9615 : Neuronal ceroid lipofuscinosis, 8 in Canis lupus familiaris (dog) |
Categories: Lysosomal storage disease , Nervous system phene
Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600143 (trait) , 607837 (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: CLN8; NCL8
History: This disorder was first reported by Koppang (1970), who established a colony of English Setters in which the disorder segregated.
Mapping: Lingaas et al. (1998) conducted a genome scan with a panel of 103 microsatellites in a pedigree of "133 animals in three families with a total of 117 offspring". Subsequent genotyping of additional animals with a targetted set of markers from the genome scan enabled Lingaas et al. (1998) to report that "Linkage analysis showed three genetic markers to be linked to the disease locus with the closest marker at a distance of about 3 CM. Two other loci were linked with these markers making a linkage group of five genetic markers. The linkage group spanned a distance of 54 CM." At this time, this linkage group had not been allocated to a particular canine chromosome. By 2005, it was known that this linkage group corresponds to a region of chromosome CFA37 (Katz et al., 2005).
Molecular basis: In one of the early uses of the initial canine genome assembly, Katz et al. (2005) conducted megablast searches of the canine genome with all eight then-known human genes for ceroid lipofuscinosos. One of these (CLN8) was shown to be located on CFA37, near to the mapped location of this disorder (see Mapping section above). Sequencing of the canine CLN8 gene in affected English Setters revealed the causative mutation to be "a T-to-C transition in the CLN8 gene that predicts a p.L164P missense mutation". Whole-genome sequencing of an affected "mixed breed dog with Australian Shepherd and Blue Heeler ancestry" enabled Guo et al. (2014) to identify a nonsense mutation in the CLN8 gene of this dog, namely c.585G>A; p.Trp195*. Genotyping of archival samples enabled these authors to confirm the causality of this mutation. Hirz et al. (2017) reported "a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases" "of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam". Lingaas et al. (2018) reported a likely causal variant in the Saluki breed, namely a "single bp insertion (c.349dupT) in exon 2, introducing an immediate stop codon (p.Glu117*)" Guo et al. (2019) reported that an affected German Shorthaired Pointer was homozygous for the same nonsense variant as described by Guo et al. (2014).
Clinical features: Koppang (1992) and Guo et al. (2014) describe the disease in English Setter and Australian Shepherd dogs: From birth to 12-14 months of age, the dog presents as healthy. At 14-18 months, visual impairment and behavioural changes indicative of neurological degeneration, such as decreased responsiveness to voice commands and compulsive circling, develop. These symptoms worsen, leading to blindness, ataxia and eventual loss of motor function in the limbs. Seizures develop at 17-24 months, becoming more frequent and severe until death or euthanasia of the animal which usually occurs before the age of 27 months. IT thanks DVM student Steven Serb, who provided the basis of this contribution in May 2023.
Pathology: Koppang (1992) and Guo et al. (2014) describe the disease in English Setter and Australian Shepherd dogs: Gross pathology as well as MRI examination of the brain identifies diffuse brain atrophy and ventriculomegaly, which progresses alongside clinical signs. Histopathology identifies the accumulation of autofluorescent lysosomal storage material in neural tissue, which is pathognomonic for NCL. IT thanks DVM student Steven Serb, who provided the basis of this contribution in May 2023.
Breeds:
Alpine Dachsbracke (Dog) (VBO_0200023),
Australian Shepherd (Dog) (VBO_0200095),
English Setter (Dog) (VBO_0200495),
German Shorthaired Pointer (Dog) (VBO_0200583),
Saluki (Dog) (VBO_0201171).
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 |
---|---|---|---|---|---|---|
CLN8 | ceroid-lipofuscinosis, neuronal 8 (epilepsy, progressive with mental retardation) | Canis lupus familiaris | 37 | NC_051841.1 (30888770..30912784) | CLN8 | 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 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
690 | Alpine Dachsbracke (Dog) | Neuronal ceroid lipofuscinosis, 8 | CLN8 | deletion, gross (>20) | Naturally occurring variant | CanFam3.1 | 37 | g.30852988_30902901del | c.-14679_*18669del | NM_001012343.1; a homozygous deletion encompassing the entire CLN8 gene | 2017 | 28024876 | g. information obtained from Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017 | |||
971 | Saluki (Dog) | Neuronal ceroid lipofuscinosis, 8 | CLN8 | insertion, small (<=20) | Naturally occurring variant | CanFam3.1 | 37 | g.30874636dupT | c.349dupT | p.(E117*) | "an insertion of 1 bp (T) in the CLN8 gene (Fig. S2) in a short T repeat, thereby changing the stretch of 9 T's to a stretch consisting of 10 T's. The exact position of the inserted base could obviously not be verified, given that this was an insertion of a single base in a stretch of nine repeats of the same base (CFA37:g.30874628–30874636). According to the recommended nomenclature, the T insertion was noted as a T duplication in the T farthest in the 3′ direction (g.30874636dupT; c.349dupT)" | 2018 | 29446145 | |||
69 | English Setter (Dog) | Neuronal ceroid lipofuscinosis, 8 | CLN8 | missense | Naturally occurring variant | CanFam3.1 | 37 | g.30874779T>C | c.491T>C | p.(L164P) | 2005 | 15629147 | Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool | |||
338 | Australian Shepherd (Dog) German Shorthaired Pointer (Dog) | Neuronal ceroid lipofuscinosis, 8 | CLN8 | nonsense (stop-gain) | Naturally occurring variant | CanFam3.1 | 37 | g.30883950G>A | c.585G>A | p.(W195*) | NM_001012343: c.585G>A (Guo et al., 2014) | 2014 | 24953404 | Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; confirmed by Guo et al. (2019, pages 3, 4, 5 and 6), assuming that the g. coordinate (g.30,895,648) in the abstract of Guo et al. (2019) is a typo. |
Cite this entry
Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:001506-9615: 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. | |
Meadows, J.R.S., Kidd, J.M., Wang, G.D., Parker, H.G., Schall, P.Z., Bianchi, M., Christmas, M.J., Bougiouri, K., Buckley, R.M., Hitte, C., Nguyen, A.K., Wang, C., Jagannathan, V., Niskanen, J.E., Frantz, L.A.F., Arumilli, M., Hundi, S., Lindblad-Toh, K., Ginja, C., Agustina, K.K., André, C., Boyko, A.R., Davis, B.W., Drögemüller, M., Feng, X.Y., Gkagkavouzis, K., Iliopoulos, G., Harris, A.C., Hytönen, M.K., Kalthoff, D.C., Liu, Y.H., Lymberakis, P., Poulakakis, N., Pires, A.E., Racimo, F., Ramos-Almodovar, F., Savolainen, P., Venetsani, S., Tammen, I., Triantafyllidis, A., vonHoldt, B., Wayne, R.K., Larson, G., Nicholas, F.W., Lohi, H., Leeb, T., Zhang, Y.P., Ostrander, E.A. : | |
Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture. Genome Biol 24:187, 2023. Pubmed reference: 37582787. DOI: 10.1186/s13059-023-03023-7. | |
2021 | 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. | |
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 | Guo, J., Johnson, G.S., Cook, J., Harris, O.K., Mhlanga-Mutangadura, T., Schnabel, R.D., Jensen, C.A., Katz, M.L. : |
Neuronal ceroid lipofuscinosis in a German Shorthaired Pointer associated with a previously reported <i>CLN8</i> nonsense variant. Mol Genet Metab Rep 21:100521, 2019. Pubmed reference: 31687336. DOI: 10.1016/j.ymgmr.2019.100521. | |
2018 | Lingaas, F., Guttersrud, O.A., Arnet, E., Espenes, A. : |
Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8. Anim Genet 49:52-58, 2018. Pubmed reference: 29446145. DOI: 10.1111/age.12629. | |
2017 | Hirz, M., Drögemüller, M., Schänzer, A., Jagannathan, V., Dietschi, E., Goebel, H.H., Hecht, W., Laubner, S., Schmidt, M.J., Steffen, F., Hilbe, M., Köhler, K., Drögemüller, C., Herden, C. : |
Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog. Mol Genet Metab 120:269-277, 2017. Pubmed reference: 28024876. DOI: 10.1016/j.ymgme.2016.12.007. | |
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. | |
2014 | Guo, J., Johnson, G.S., Brown, H.A., Provencher, M.L., da Costa, R.C., Mhlanga-Mutangadura, T., Taylor, J.F., Schnabel, R.D., O'Brien, D.P., Katz, M.L. : |
A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 112:302-9, 2014. Pubmed reference: 24953404. DOI: 10.1016/j.ymgme.2014.05.014. | |
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. | |
2005 | Katz, ML., Khan, S., Awano, T., Shahid, SA., Siakotos, AN., Johnson, GS. : |
A mutation in the CLN8 gene in English Setter dogs with neuronal ceroid-lipofuscinosis. Biochem Biophys Res Commun 327:541-7, 2005. Pubmed reference: 15629147. DOI: 10.1016/j.bbrc.2004.12.038. | |
2002 | Jolly, R.D., Brown, S., Das, A.M., Walkley, S.U. : |
Mitochondrial dysfunction in the neuronal ceroid-lipofuscinoses (Batten disease). Neurochem Int 40:565-71, 2002. Pubmed reference: 11850114. DOI: 10.1016/s0197-0186(01)00128-0. | |
2001 | Katz, M.L., Shibuya, H., Johnson, G.S. : |
Animal models for the ceroid lipofuscinoses. Adv Genet 45:183-203, 2001. Pubmed reference: 11332773. | |
Siakotos, A.N., Hutchins, G.D., Farlow, M.R., Katz, M.L. : | |
Assessment of dietary therapies in a canine model of Batten disease. Eur J Paediatr Neurol 5 Suppl A:151-6, 2001. Pubmed reference: 11588988. DOI: 10.1053/ejpn.2000.0453. | |
1998 | Lingaas, F., Aarskaug, T., Sletten, M., Bjerkas, I., Grimholt, U., Moe, L., Juneja, R.K., Wilton, A.N., Galibert, F., Holmes, N.G., Dolf, G. : |
Genetic markers linked to neuronal ceroid lipofuscinosis in English Setter dogs Animal Genetics 29:371-376, 1998. Pubmed reference: 9800325. | |
Shibuya, H., Liu, P.C., Katz, M.L., Siakotos, A.N., Nonneman, D.J., Johnson, G.S. : | |
Coding sequence and exon/intron organization of the canine CLN3 (Batten-disease) gene and its exclusion as the locus for ceroid-lipofuscinosis in English Setter dogs Journal of Neuroscience Research 52:268-275, 1998. Pubmed reference: 9590435. | |
Siakotos, A.N., Blair, P.S., Savill, J.D., Katz, M.L. : | |
Altered mitochondrial function in canine ceroid-lipofuscinosis Neurochemical Research 23:983-989, 1998. Pubmed reference: 9690741. | |
1997 | Nilsson, S.E., Wrigstad, A. : |
Electrophysiology in some animal and human hereditary diseases involving the retinal pigment epithelium. Eye (Lond) 11 ( Pt 5):698-706, 1997. Pubmed reference: 9474321. DOI: 10.1038/eye.1997.180. | |
1995 | Katz, M.L., Siakotos, A.N. : |
Canine hereditary ceroid-lipofuscinosis: Evidence for a defect in the carnitine biosynthetic pathway American Journal of Medical Genetics 57:266-271, 1995. Pubmed reference: 7668343. DOI: 10.1002/ajmg.1320570231. | |
Kitani, K., Senda, M., Toyama, H., Miyasaka, K., Kanai, S., Ohta, M., Ivy, G.O., Koppang, N. : | |
Decline in glucose metabolism in the brain in neuronal ceroid lipofuscinosis (NCL) in English setter--evidence by positron emission tomography (PET). Gerontology 41 Suppl 2:249-57, 1995. Pubmed reference: 8821336. DOI: 10.1159/000213747. | |
Savill, J., Azzarelli, B., Siakotos, A.N. : | |
Early detection of canine ceroid-lipofuscinosis (CCL): An ultrastructural study American Journal of Medical Genetics 57:250-253, 1995. Pubmed reference: 7668340. DOI: 10.1002/ajmg.1320570228. | |
Siakotos, A.N., Schnippel, K., Lin, R.C., Vankuijk, F.J.G.M. : | |
Biosynthesis and metabolism of 4-hydroxynonenal in canine ceroid-lipofuscinosis American Journal of Medical Genetics 57:290-293, 1995. Pubmed reference: 7668347. DOI: 10.1002/ajmg.1320570235. | |
1994 | Dunn, W.A., Raizada, M.K., Vogt, E.S., Brown, E.A. : |
Growth factor-induced neurite growth in primary neuronal cultures of dogs with neuronal ceroid lipofuscinosis Int J Dev Neurosci 12:185-96, 1994. Pubmed reference: 7942092. DOI: 10.1016/0736-5748(94)90040-x. | |
Katz, M.L., Christianson, J.S., Norbury, N.E., Gao, C.L., Siakotos, A.N., Koppang, N. : | |
Lysine methylation of mitochondrial ATP synthase subunit-c stored in tissues of dogs with hereditary ceroid lipofuscinosis. J Biol Chem 269:9906-11, 1994. Pubmed reference: 8144584. | |
1992 | Banerjee, P., Dasgupta, A., Siakotos, A.N., Dawson, G. : |
Evidence for lipase abnormality: high levels of free and triacylglycerol forms of unsaturated fatty acids in neuronal ceroid-lipofuscinosis tissue. Am J Med Genet 42:549-54, 1992. Pubmed reference: 1609837. DOI: 10.1002/ajmg.1320420426. | |
Goebel, H.H. : | |
Retina in various animal models of neuronal ceroid-lipofuscinosis. Am J Med Genet 42:605-8, 1992. Pubmed reference: 1609843. DOI: 10.1002/ajmg.1320420435. | |
Koppang, N. : | |
English Setter model and juvenile ceroid-lipofuscinosis in man. American Journal of Medical Genetics 42:599-604, 1992. Pubmed reference: 1609842. DOI: 10.1002/ajmg.1320420434. | |
1990 | Deeg, H.J., Shulman, H.M., Albrechtsen, D., Graham, T.C., Storb, R., Koppang, N. : |
Battens disease - Failure of allogeneic bone marrow transplantation to arrest disease progression in a canine model. Clin Genet 37:264-70, 1990. Pubmed reference: 2350897. DOI: 10.1111/j.1399-0004.1990.tb04188.x. | |
1988 | Koppang, N. : |
The English setter with ceroid-lipofuscinosis: a suitable model for the juvenile type of ceroid-lipofuscinosis in humans. Am J Med Genet Suppl 5:117-25, 1988. Pubmed reference: 3146311. | |
Siakotos, A.N., Bray, R., Dratz, E., van Kuijk, F., Sevanian, A., Koppang, N. : | |
4-Hydroxynonenal: a specific indicator for canine neuronal-retinal ceroidosis. Am J Med Genet Suppl 5:171-81, 1988. Pubmed reference: 3146315. | |
1987 | Koppang, N. : |
Hereditary ceroid lipofuscinosis in English setter dogs. A model for human neuronal ceroid-lipofuscinosis and aging. Advances in Biosciences 64:185-195, 1987. | |
1984 | Keller, R.K., Armstrong, D., Crum, F.C., Koppang, N. : |
Dolichol and dolichyl phosphate levels in brain tissue from English setters with ceroid lipofuscinosis. J Neurochem 42:1040-7, 1984. Pubmed reference: 6321656. DOI: 10.1111/j.1471-4159.1984.tb12708.x. | |
1983 | Nilsson, S.E., Armstrong, D., Koppang, N., Persson, P., Milde, K. : |
Studies on the retina and the pigment epithelium in hereditary canine ceroid lipofuscinosis. IV. Changes in the electroretinogram and the standing potential of the eye. Invest Ophthalmol Vis Sci 24:77-84, 1983. Pubmed reference: 6681808. | |
1980 | Armstrong, D., Neville, H., Siakotos, A., Wilson, B., Wehling, C., Koppang, N. : |
Morphological and biochemical abnormalities in a model of retinal degeneration: Canine ceroid-lipofuscinosis (CCL). Neurochem Int 1C:405-26, 1980. Pubmed reference: 20487751. DOI: 10.1016/0197-0186(80)90076-5. | |
Neville, H., Armstrong, D., Wilson, B., Koppang, N., Wehling, C. : | |
Studies on the retina and the pigment epithelium in hereditary canine ceroid lipofuscinosis. III. Morphologic abnormalities in retinal neurons and retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 19:75-86, 1980. Pubmed reference: 7350137. | |
1975 | Berson, E.L., Watson, G. : |
Electroretinograms in English Setters with neuronal ceroid lipofuscinosis Investigative Ophthalmology and Visual Science 19:87-90, 1975. | |
1970 | Koppang, N. : |
Neuronal ceroid-lipofuscinosis in English setters Journal of Small Animal Practice 10:639-644, 1970. |
Edit History
- Created by Frank Nicholas on 26 Oct 2010
- Changed by Frank Nicholas on 12 Dec 2011
- Changed by Frank Nicholas on 22 Oct 2012
- Changed by Frank Nicholas on 18 Jun 2013
- Changed by Frank Nicholas on 15 Sep 2014
- Changed by Frank Nicholas on 31 Dec 2016
- Changed by Frank Nicholas on 14 Mar 2017
- Changed by Frank Nicholas on 14 Aug 2017
- Changed by Frank Nicholas on 22 Feb 2018
- Changed by Frank Nicholas on 03 Feb 2020
- Changed by Imke Tammen2 on 11 Jun 2023