Abstract
Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 – 43.36–43.38 Mb and SLC19A3.1 – 43.411–43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.
Highlights
Alaskan Husky Encephalopathy (AHE) is a fatal brain disease in young Alaskan Husky (AH) dogs, often affecting multiple dogs from the same litter [1,2]
Clinical Findings and Outcome in dogs with AHE All 11 dogs with AHE included in this study showed typical clinical signs (Table 1), as well as MR imaging (Figure 1) and/or neuropathological features of AHE in the brain (Figure 2)
We have demonstrated in this study that a homozygous mutation in the SLC19A3.1 gene encoding a thiamine transport protein is strongly associated with AHE
Summary
Alaskan Husky Encephalopathy (AHE) is a fatal brain disease in young Alaskan Husky (AH) dogs, often affecting multiple dogs from the same litter [1,2]. AHE was initially described in 13 dogs from the northern United States, including Alaska, Massachusetts, New York, Wyoming, Maine and Minnesota [1]. Based on the clinical and neuropathological similarities to Leigh Syndrome (LS) in people, AHE was proposed to be a mitochondrial encephalopathy. Dogs with AHE may have acute onset of clinical signs, or chronic progressive waxing and waning clinical history. 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
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