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

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.

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

“…Similar to human patients, affected dogs show bilateral symmetrical lesions affecting the gray matter in specific areas of the brain and spinal cord, but the exact distribution of the lesions within the neuraxis varies between the different breeds. For example, the thalamus is commonly affected in Alaskan huskies and Yorkshire terriers with variants in SLC19A3 and was not affected in the dogs from this report 6 , 7 . Interestingly, bilateral symmetrical changes affecting the cerebellar nuclei were reported in Bullmastiff dogs with a variant in the MFF gene encoding mitochondrial fission factor 31 .…”

“…In dogs, clinical phenotypes sharing similarities with Leigh syndrome have been reported in American Staffordshire bull terriers 26 , 27 , Alaskan huskies 6 , Yorkshire terriers 7 , Australian cattle dog 28 , a Shih Tzu 29 and a mixed-breed dog 30 . Canine cases tend to present at an early age with most reported cases being younger than 1.5 years of age 6 , 7 , 26 – 30 .…”

“…In dogs, clinical phenotypes sharing similarities with Leigh syndrome have been reported in American Staffordshire bull terriers 26 , 27 , Alaskan huskies 6 , Yorkshire terriers 7 , Australian cattle dog 28 , a Shih Tzu 29 and a mixed-breed dog 30 . Canine cases tend to present at an early age with most reported cases being younger than 1.5 years of age 6 , 7 , 26 – 30 . Similar to human patients, affected dogs show bilateral symmetrical lesions affecting the gray matter in specific areas of the brain and spinal cord, but the exact distribution of the lesions within the neuraxis varies between the different breeds.…”

“…In Alaskan Huskies, an SLC19A3 :c.624delinsTGCAA variant leads to multifocal CNS disease with seizures, neurological deficits, blindness, and dysphagia 6 . The same gene is affected in Yorkshire terriers with juvenile-onset necrotizing encephalopathy, for which a homozygous c.205_210delins35 variant was identified in affected dogs 7 .…”

An Overview of Canine Inherited Neurological Disorders with Known Causal Variants

“…Clinical signs have an acute onset and include multifocal central nervous system deficits such as altered mentation, seizures, absent menace response, central blindness, dysphagia, hypermetria, proprioceptive positioning deficits, ataxia, tetraparesis, and facial hypoalgesia. For the Alaskan Husky, the likely causal variant was a 4 bp insertion (c.624insTTGC) and SNP (c.625C>A) in the exon 2 of the SLC19A3 gene, while, for the Yorkshire Terrier, the indel affecting ~45 bp was located in exon 2 of the same gene [156,157].…”