SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy

Genes (Basel). 2020 Oct 16;11(10):1215. doi: 10.3390/genes11101215.

Abstract

Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological analysis revealed the presence of major characteristics of human Leigh syndrome and SNE in Alaskan huskies. The aim of this study was to characterize the genetic etiology of SNE-affected purebred Yorkshire terriers. After SNP genotyping and subsequent homozygosity mapping, we identified a single loss-of-function variant by whole-genome sequencing in the canine SLC19A3 gene situated in a 1.7 Mb region of homozygosity on chromosome 25. All ten cases were homozygous carriers of a mutant allele, an indel variant in exon 2, that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence. This study reports a most likely pathogenic variant in SLC19A3 causing a form of SNE in Yorkshire terriers and enables selection against this fatal neurodegenerative recessive disorder. This is the second report of a pathogenic alteration of the SLC19A3 gene in dogs with SNE.

Keywords: Canis familiaris; neurometabolic disorder; precision medicine; rare disease; whole-genome sequencing.

MeSH terms

  • Animals
  • Breeding
  • Dogs
  • Female
  • Leigh Disease / genetics*
  • Leigh Disease / pathology
  • Loss of Function Mutation*
  • Male
  • Membrane Transport Proteins / genetics*
  • Pedigree
  • Whole Genome Sequencing

Substances

  • Membrane Transport Proteins
  • SLC19A3 protein, human