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: