OMIA:001097-9615 : Necrotising encephalopathy, subacute, of Leigh in Canis lupus familiaris (dog) |
In other species: taurine cattle
Categories: Nervous system phene
Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606152 (gene) , 607483 (trait)
Single-gene trait/disorder: yes
Mode of inheritance: Autosomal recessive
Disease-related: yes
Key variant known: yes
Year key variant first reported: 2013
Cross-species summary: Also known as juvenile-onset necrotizing/necrotising encephalopathy (SNE)
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) Drögemüller et al. (2020) identified the likely cause of ten "SNE-affected purebred Yorkshire terriers" as "an indel variant in exon 2 [of the SLC19A3 gene], that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence".
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."
Breeds:
Alaskan Husky (Dog) (VBO_0200015),
Yorkshire Terrier (Dog) (VBO_0201448).
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 |
---|---|---|---|---|---|---|
SLC19A3 | solute carrier family 19 (thiamine transporter), member 3 | Canis lupus familiaris | 25 | NC_051829.1 (40695609..40657948) | SLC19A3 | 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 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
578 | Alaskan Husky (Dog) | Necrotising encephalopathy, subacute, of Leigh | SLC19A3 | delins, small (<=20) | Naturally occurring variant | CanFam3.1 | 25 | g.40417443delinsTTGCA | c.624delinsTGCAA | p.(Q208Hfs*13) | XM_022409850.1; XP_022265558.1; published as c.624 insTTGC, c.625 C>A; coordinates in the table have been updated to reflect HGVS nomenclature | 2013 | 23469184 | Genomic coordinates in CanFam3.1 provided by Robert Kuhn. | ||
1250 | Yorkshire Terrier (Dog) | Juvenile-onset necrotizing encephalopathy | SLC19A3 | delins, gross (>20) | Naturally occurring variant | CanFam3.1 | 25 | g.40417857_40417862delinsN[35] | c.205_210delinsN[35] | p.(P69Ifs*45) | XM_022409850.1; XP_022265558.1; "a 35 bp insertion replacing 6 bp and thereby disturbing the correct reading frame" (Drögemüller et al., 2020) | 2020 | 33081289 |
Cite this entry
Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001097-9615: 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. | |
2021 | Thorsrud, J.A., Huson, H.J. : |
Description of breed ancestry and genetic health traits in arctic sled dog breeds. Canine Med Genet 8:8, 2021. Pubmed reference: 34544496. DOI: 10.1186/s40575-021-00108-z. | |
2020 | Drögemüller, M., Letko, A., Matiasek, K., Jagannathan, V., Corlazzoli, D., Rosati, M., Jurina, K., Medl, S., Gödde, T., Rupp, S., Fischer, A., Luján Feliu-Pascual, A., Drögemüller, C. : |
SLC19A3 loss-of-function variant in Yorkshire terriers with Leigh-like subacute necrotizing encephalopathy. Genes (Basel) 11:1215, 2020. Pubmed reference: 33081289. DOI: 10.3390/genes11101215. | |
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
- Changed by Frank Nicholas on 15 May 2020
- Changed by Frank Nicholas on 23 Oct 2020
- Changed by Imke Tammen2 on 03 Oct 2021
- Changed by Imke Tammen2 on 15 Jun 2024