SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy.
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.
['Drögemüller|Michaela|M|', 'Letko|Anna|A|0000-0002-6521-1285', 'Matiasek|Kaspar|K|', 'Jagannathan|Vidhya|V|0000-0002-8155-0041', 'Corlazzoli|Daniele|D|', 'Rosati|Marco|M|', 'Jurina|Konrad|K|', 'Medl|Susanne|S|', 'Gödde|Thomas|T|', 'Rupp|Stefan|S|', 'Fischer|Andrea|A|', 'Luján Feliu-Pascual|Alejandro|A|0000-0002-3555-9248', 'Drögemüller|Cord|C|0000-0001-9773-522X']
D000818:Animals D001947:Breeding D004285:Dogs D005260:Female D007888:Leigh Disease D000073658:Loss of Function Mutation D008297:Male D026901:Membrane Transport Proteins D010375:Pedigree D000073336:Whole Genome Sequencing
whole-genome sequencing Canis familiaris neurometabolic disorder precision medicine rare disease