An intronic variant in Ferredoxin Reductase (FDXR) creates a cryptic exon in Quarter Horses with Equine Juvenile Spinocerebellar Ataxia

Equine Juvenile Spinocerebellar Ataxia (EJSCA) is a novel autosomal recessive neurologic disease in Quarter Horses. Affected foals display a progressive proprioceptive ataxia by 1-5 weeks of age, leading to recumbency and necessitating euthanasia. Whole genome sequencing was performed on 7 EJSCA cases and unaffected horses that included 4 obligate carriers, 4 unaffected half or full-siblings, and 28 unrelated, unaffected control Quarter Horses. An 82 kb region of association was identified (EquCab3.0, chr11: 6963986-7045999), containing 9 candidate SNPs across four genes (FADS6, FDXR, GRIN2C and TMEM104). Decreased FDXR mRNA expression and a cryptic exon was identified in spinal cord tissue from EJSCA cases via RNA-sequencing. One of the 9 associated SNPs (FDXR-203 c.177 + 1778G > C) was the eighth base pair of this cryptic exon. Affected foals were all homozygous for the variant. Protein concentrations of FDXR were lower in EJSCA cases in spinal cord and liver compared to unaffected controls. The FDXR-203 c.177 + 1778G > C mutation represents the first non-coding neurological genetic variant in horses. Additionally, this is the first genetic cause of a degenerative axonopathy in the horse and a spontaneous disease model to study FDXR pathology in humans.