OMIA 001552-9615 : Neuronal ceroid lipofuscinosis, 12 in Canis lupus familiaris

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2011

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. In the Tibetan terrier, changes in behavior and vision begin at 4-6 years of age. A genetic test is available.

Mapping: By conducting a GWAS on 19 affected and 15 control Tibetan Terriers, each genotyped with the Affymetrix Canine Genome 2.0 Array, Farias et al. (2011) mapped this disorder to a 1.3 Mb region of chromosome CFA2., which contains 18 genes, including a likely candidate ATP13A2.

Later that same year, Wöhlke et al. (2011) reported an independent GWAS on 12 affected and 7 control Tibetan Terriers, each genotyped with the "127K canine Affymetrix SNP chip", which enabled them to map this disorder to the same region of CFA2 as Farias et al. (2011).

Molecular basis: By sequencing the likely positional candidate gene mentioned in the Mapping section (above), Farias et al (2011) identified the causative mutation as a single base deletion in ATP13A2, namely "c.1,623delG, which predicted a frame shift and premature termination codon (p.P541fsX597)".

Later that same year, Wöhlke et al. (2011) confirmed the same mutation, but called it c.1620delG, and stated that it "causes an alternative splicing of exon 16 but not a frameshift mutation with a premature termination codon as previously supposed [by Farias et al., 2011]". They went on to explain that "As a result of the in-frame loss of exon 16, the ATP13A2 protein is shortened by 69 amino acids. Therefore, all NCL-affected Tibetan terriers in the present study can synthesize this shortened ATP13A2 protein. In humans, all three isoforms do not lack exon 16. This new insight on the structure of the mutated protein may explain why Tibetan terriers express only mild neurodegenerative symptoms and the onset of the disease is late in life."

Clinical features: Behavioral signs usually appear around 4 to 6 years of age (Katz et al., 2005, Katz et al., 2007, Farias et al., 2011). Signs include behavioral changes, cognitive decline, cerebellar ataxia, dementia, seizures, nervousness, aggressiveness, loss of training, hypersensitivity to stimuli, loss of coordination, tremors, retinal degeneration, depressed rod function, some impairment of cone function, moderate visual impairment in low light, but good visual acuity in bright light.

Pathology: There is widespread accumulation of autofluorescent lysosomal storage material throughout the cerebral cortex, retina, and cerebellum. Stored material appears as stacks of membranes in whorls or parallel arrays, or coarsely granular and lipid-like substances. Components of this material include glial fibrillary acidic protein (GFAP), and histone H4 (Katz et al., 2007).

Prevalence: As NCL is rare in other breeds, it is more common by comparison in the Tibetan terrier, which is likely due to the relatively small breeding population and adult onset of signs (Katz et al., 2005).

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

Genetic testing: There is a test available.

Breed: Tibetan Terrier.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ATP13A2 ATPase type 13A2 Canis lupus familiaris 2 NC_006584.3 (81196355..81215736) ATP13A2 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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
Tibetan Terrier Neuronal ceroid lipofuscinosis, 12 ATP13A2 splicing c.1620delG Originally c.1623delG p.P541fs*597 (Farias et al., 2011); revised coordinates from Wöhlke et al. (2011) 2011 21362476 22022275 Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017 present the original coordinates rather than the revised ones, with no explanation.

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.
2011 Farias, F.H., Zeng, R., Johnson, G.S., Wininger, F.A., Taylor, J.F., Schnabel, R.D., McKay, S.D., Sanders, D.N., Lohi, H., Seppälä, E.H., Wade, C.M., Lindblad-Toh, K., O'Brien, D.P., Katz, M.L. :
A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers. Neurobiol Dis 42:468-74, 2011. Pubmed reference: 21362476. DOI: 10.1016/j.nbd.2011.02.009.
Wöhlke, A., Philipp, U., Bock, P., Beineke, A., Lichtner, P., Meitinger, T., Distl, O. :
A one base pair deletion in the canine ATP13A2 gene causes exon skipping and late-onset neuronal ceroid lipofuscinosis in the Tibetan terrier. PLoS Genet 7:e1002304, 2011. Pubmed reference: 22022275. DOI: 10.1371/journal.pgen.1002304.
2007 Katz, ML., Sanders, DN., Mooney, BP., Johnson, GS. :
Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis. J Inherit Metab Dis 30:952-63, 2007. Pubmed reference: 18004671. DOI: 10.1007/s10545-007-0683-y.
2005 Drogemulller, C., Wohlke, A., Distl, O. :
Evaluation of the canine TPP1 gene as a candidate for neuronal ceroid lipofuscinosis in Tibetan Terrier and Polish Owczarek Nizinny dogs. Anim Genet 36:178-9, 2005. Pubmed reference: 15771740. DOI: 10.1111/j.1365-2052.2005.01254.x.
Katz, ML., Narfstrom, K., Johnson, GS., O'Brien, DP. :
Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-lipofuscinosis. Am J Vet Res 66:67-76, 2005. Pubmed reference: 15691038.
2002 Katz, M.L., Sanders, D.A., Sanders, D.N., Hansen, E.A., Johnson, G.S. :
Assessment of plasma carnitine concentrations in relation to ceroid lipofuscinosis in Tibetan Terriers. Am J Vet Res 63:890-5, 2002. Pubmed reference: 12061538.
1992 Alroy, J., Schelling, SH., Thalhammer, JG., Raghavan, SS., Natowicz, MR., Prence, EM., Orgad, U. :
Adult onset lysosomal storage disease in a Tibetan terrier: clinical, morphological and biochemical studies. Acta Neuropathol 84:658-63, 1992. Pubmed reference: 1471473.
Riis, R.C., Cummings, J.F., Loew, E.R., Delahunta, A. :
Tibetan Terrier Model of Canine Ceroid Lipofuscinosis American Journal of Medical Genetics 42:615-621, 1992. Pubmed reference: 1609844. DOI: 10.1002/ajmg.1320420437.

Edit History


  • Created by Frank Nicholas on 04 Mar 2011
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 21 May 2013
  • Changed by Frank Nicholas on 20 Aug 2013