OMIA 001504-9615 : Neuronal ceroid lipofuscinosis, 1 in Canis lupus familiaris
Edited by Vicki N. Meyers-Wallen, VMD, PhD, Dipl. ACTMapping: CFA15 Molecular basis: A causative mutation in Dachshunds is a single nucleotide insertion (c.736-737insC) in exon 8 of PPT1, which causes a frameshift in amino acid codons and a premature stop codon. The resultant truncated PPT1 protein lacks a hydrophobic region that is key to enzyme activity, such that the affected dachshund brain has only 3% activity of normal dogs (Sanders et al., 2010).
Whole-genome sequencing of an affected Cane Corso dog by Kolicheski et al. (2017) revealed the likely causal variant to be "a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos."Clinical features: Diffuse retinal thinning and severe retinal vessel degeneration were present at 7 months of age, followed by complete blindness at 8 months of age (Sanders et al., 2010). Additional signs appeared at nine months of age, including disorientation, ataxia, weakness, visual impairment, and behavioral changes. These progressed to kyphosis and stiffness in gait, uncontrolled rhythmic head movements, inability to recognize the owner, severe vision loss, sensitivity to loud noise, inappropriate vocalization, circling, loss of coordination and general weakness. There is no effective treatment. Pathology: The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases characterized by intraneuronal accumulation of fluorescent granules, early neuronal death, and progressive neurodegeneration of the central nervous system. Affected dogs are severely deficient in palmitoyl protein thioesterase (PPT1), a key enzyme in creating hydrophobic regions in proteins, allowing them to interact with membranes, participate in vesicular transport and signal transduction, and maintain cellular architecture. As a result of severely deficient PPT1 activity, autofluorescent material accumulates in neuronal lysosomes of the retina, cerebellum, and cerebral cortex, followed by progressive neurodegeneration (Sanders et al., 2010). The central retina maintains its normal thickness and structure, and has inclusions in many retinal layers, including photoreceptor inner segments, outer nuclear layer, and ganglion cell layer. The peripheral retina appears significantly thinned with loss of the photoreceptor cell layer and absence of normal structural layering (Sanders et al., 2010). Storage material is widely abundant in the cerebral cortex and cerebellum. In the latter, increased concentration was identified in the granular layer with little or no accumulation in Purkinje cells (Sanders et al., 2010). Prevalence: Thus far, one affected animal and three carriers from the same pedigree have been identified (Sanders et al., 2010). Control: Parents of affected dogs are obligate carriers. Siblings of affected animals should be tested. Breeding of affected or carrier dogs is not recommended. Genetic testing: A test is available to detect the causative mutation in Dachshunds. Breeds: Dachshund, Italian Cane Corso. Associated gene:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|PPT1||palmitoyl-protein thioesterase 1||Canis lupus familiaris||15||NC_006597.3 (2815428..2886474)||PPT1||Homologene, Ensembl, NCBI gene|
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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.
|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|
|Dachshund||Neuronal ceroid lipofuscinosis, 1||PPT1||insertion, small (<=20)||c.736-737insC||p.F246Lfs*29||2010||20494602||p. information obtained fromÂ Katz et al. (2017) Neurobiol Dis. doi: 10.1016/j.nbd.2017.08.017|
|Italian Cane Corso||Neuronal ceroid lipofuscinosis, 1||PPT1||splicing||CanFam3.1||15||g.2860424||c.124 + 1G>A||2017||28008682|
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.|
|Kolicheski, A., Barnes Heller, H.L., Arnold, S., Schnabel, R.D., Taylor, J.F., Knox, C.A., Mhlanga-Mutangadura, T., O'Brien, D.P., Johnson, G.S., Dreyfus, J., Katz, M.L. :|
|Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis. J Vet Intern Med 31:149-157, 2017. Pubmed reference: 28008682. DOI: 10.1111/jvim.14632.|
|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.|
|2010||Bellettato, C.M., Scarpa, M. :|
|Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33:347-62, 2010. Pubmed reference: 20429032. DOI: 10.1007/s10545-010-9075-9.|
|Sanders, DN., Farias, FH., Johnson, GS., Chiang, V., Cook, JR., O'Brien, DP., Hofmann, SL., Lu, JY., Katz, ML. :|
|A mutation in canine PPT1 causes early onset neuronal ceroid lipofuscinosis in a Dachshund. Mol Genet Metab 100:349-56, 2010. Pubmed reference: 20494602. DOI: 10.1016/j.ymgme.2010.04.009.|
- Created by Frank Nicholas on 26 Oct 2010
- Changed by Martha MaloneyHuss on 23 Aug 2011
- Changed by Vicki Meyers-Wallen on 18 Sep 2011
- Changed by Frank Nicholas on 12 Dec 2011
- Changed by Frank Nicholas on 31 Dec 2016
- Changed by Frank Nicholas on 12 Jul 2018