OMIA 001097-9615 : Necrotising encephalopathy, subacute, of Leigh in Canis lupus familiaris

In other species: cattle

Possibly relevant human trait(s) and/or gene(s) (MIM number): 161700

Mendelian trait/disorder: unknown

Considered a defect: yes

Year key variant first reported: 2013

Species-specific name: Alaskan Husky Encephalopathy (AHE)

History: The first report of this disorder in dogs was in Yorkshire Terriers, by Sawashima et al. (1996). The first report in Alaskan Huskies was by Wakshlag et al. (1999).

Mapping: A GWAS was conducted by Vernau et al. (2013) on 8 affected Alaskan Huskies and 20 unaffected, related controls, each genotyped with the Illumina HD canine array, yielding 114,613 SNPs that were included in the analysis. The analysis highlighted one region on chromosome CFA25. Homozygosity mapping narrowed the region to "3.5 Mb between 41074763 and 44542154".

Molecular basis: The most likely positional candidate gene in the CFA region (see Mapping section) was SLC19A3, which "controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2" (Vernau et al., 2013). Having determined that this gene is duplicated in that region of the dog genome, Vernau et al. (2013) showed that the first of these, SLC19A3.1, has a higher sequence similarity to the corresponding human gene, and, unlike the second, is expressed in relevant tissues, namely cerebrum, cerebellum and spinal cord. Sequencing of the coding regions of SLC19A3.1 in affected dogs and in one control revealed four differences, one of which, a frameshifting "4 bp insertion (c.624 insTTGC) and SNP (c.625 C>A) in exon 2", was subsequently shown to segregate perfectly with the disorder genotype, and to not be present in other breeds: "All 11 dogs with AHE were homozygous for the mutation, 26/41 unaffected AH dogs were homozygous wild type and 15/41 unaffected AH dogs were determined to be heterozygous carriers. In order to determine if the insertion was just a polymorphism, 187 dogs from 51 breeds were genotyped and the mutant allele was not identified." (Vernau et al., 2013)

Clinical features: As summarised by Vernau et al. (2013), "Dogs with AHE may have acute onset of clinical signs, or chronic progressive waxing and waning clinical history. Typically, they have multifocal central nervous system deficits including seizures, altered mentation, dysphagia, absent menace response, central blindness, hypermetria, proprioceptive positioning deficits, facial hypoalgesia, ataxia and tetraparesis."

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SLC19A3 solute carrier family 19 (thiamine transporter), member 3 Canis lupus familiaris 25 NC_006607.3 (40442183..40411489) SLC19A3 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
Alaskan Husky Necrotising encephalopathy, subacute, of Leigh SLC19A3 insertion, small (<=20) c.624 insTTGC 2013 23469184

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.
2015 Vernau, K., Napoli, E., Wong, S., Ross-Inta, C., Cameron, J., Bannasch, D., Bollen, A., Dickinson, P., Giulivi, C. :
Thiamine Deficiency-Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1. Brain Pathol 25:441-53, 2015. Pubmed reference: 25117056. DOI: 10.1111/bpa.12188.
2013 Vernau, K.M., Runstadler, J.A., Brown, E.A., Cameron, J.M., Huson, H.J., Higgins, R.J., Ackerley, C., Sturges, B.K., Dickinson, P.J., Puschner, B., Giulivi, C., Shelton, G.D., Robinson, B.H., DiMauro, S., Bollen, A.W., Bannasch, D.L. :
Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PLoS One 8:e57195, 2013. Pubmed reference: 23469184. DOI: 10.1371/journal.pone.0057195.
2009 Baiker, K., Hofmann, S., Fischer, A., Gödde, T., Medl, S., Schmahl, W., Bauer, M.F., Matiasek, K. :
Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA. Acta Neuropathol 118:697-709, 2009. Pubmed reference: 19466433. DOI: 10.1007/s00401-009-0548-6.
2000 Brenner, O., Wakshlag, J.J., Summers, B.A., de, Lahunta, A. :
Alaskan Husky encephalopathy - a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome) Acta Neuropathologica 100:50-62, 2000. Pubmed reference: 10912920.
1999 Wakshlag, J.J., de, Lahunta, A., Robinson, T., Cooper, B.J., Brenner, O., O'Toole, T.D., Olson, J., Beckman, K.B., Glass, E., Reynolds, A.J. :
Subacute necrotising encephalopathy in an Alaskan husky Journal of Small Animal Practice 40:585-589, 1999. Pubmed reference: 10664957.
1996 Sawashima, Y., Sawashima, K., Taura, Y., Shimada, A., Umemura, T. :
Clinical and pathological findings of a Yorkshire terrier affected with necrotizing encephalitis Journal of Veterinary Medical Science 58:659-661, 1996. Pubmed reference: 8844603.

Edit History


  • Created by Frank Nicholas on 06 Sep 2005
  • Changed by Frank Nicholas on 20 May 2013
  • Changed by Frank Nicholas on 17 Jun 2013