OMIA 001552-9615 : Neuronal ceroid lipofuscinosis, 12 in Canis lupus familiaris
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."
Schmutz et al. (2019): "Whole genome sequence analysis of one of [three affected Australian Cattle] . . . dogs revealed a homozygous c.1118C > T variant in ATP13A2 that predicts a nonconservative p.(Thr373Ile) amino acid substitution. All 3 affected dogs were homozygous for this variant, which was heterozygous in 42 of 394 unaffected Australian Cattle Dogs, the remainder of which were homozygous for the c.1118C allele. "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).
Schmutz et al. (2019) "genotyped the [c.1118C>T] variant in a cohort of 397 Australian Cattle Dogs, which included the 3 known cases, dog D, 26 unaffected Australian Cattle Dogs older than 6 years of age and 367 population controls. This revealed a perfect association of the genotypes with the phenotype (Table 2). All three affected dogs carried the variant in homozygous state. Dog D, the sire of the two affected dogs was heterozygous (obligate carrier). Among the other 393 Australian Cattle dogs, we observed 352 dogs that were homozygous wildtype and 41 dogs that were heterozygous and presumably carriers for the disease. These data indicate that among the Australian Cattle Dogs that were sampled, the carrier frequency is around 10%. Because of sampling bias in our population, the carrier frequency among all Australian Cattle Dogs may be different. We also genotyped 555 dogs from genetically diverse breeds. None of these dogs carried the ATP13A2:c.1118C > T variant".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|
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.
|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.|
|Australian Cattle Dog||Neuronal ceroid lipofuscinosis, 12||ATP13A2||missense||CanFam3.1||2||g.81,208,162C>T||c.1118C>T||p.(Thr373Ile)||Schmutz et al. (2019): "The ATP13A2 variant was a missense variant, XM_005617949.3:c.1118C > T, predicted to result in a non-conservative exchange of a threonine into an isoleucine, XP_005618006.1:p.(Thr373Ile)"||2019||30956123|
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.
|2019||Schmutz, I., Jagannathan, V., Bartenschlager, F., Stein, V.M., Gruber, A.D., Leeb, T., Katz, M.L. :|
|ATP13A2 missense variant in Australian Cattle Dogs with late onset neuronal ceroid lipofuscinosis. Mol Genet Metab :, 2019. Pubmed reference: 30956123. DOI: 10.1016/j.ymgme.2018.11.015.|
|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.|
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