A Missense Mutation in the Vacuolar Protein Sorting 11 (<i>VPS11</i>) Gene Is Associated with Neuroaxonal Dystrophy in Rottweiler Dogs

Abstract

Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of young adult Rottweiler dogs (<i>Canis lupus familiaris</i>) characterized pathologically by axonal spheroids primarily targeting sensory axon terminals. A genome-wide association study of seven Rottweilers affected with NAD and 42 controls revealed a significantly associated region on canine chromosome 5 (CFA 5). Homozygosity within the associated region narrowed the critical interval to a 4.46 Mb haplotype (CFA5:11.28 Mb - 15.75 Mb; CanFam3.1) that associated with the phenotype. Whole-genome sequencing of two histopathologically confirmed canine NAD cases and 98 dogs unaffected with NAD revealed a homozygous missense mutation within the Vacuolar Protein Sorting 11 (<i>VPS11</i>) gene (g.14777774T > C; p.H835R) that was associated with the phenotype. These findings present the opportunity for an antemortem test for confirming NAD in Rottweilers where the allele frequency was estimated at 2.3%. <i>VPS11</i> mutations have been associated with a degenerative leukoencephalopathy in humans, and <i>VSP11</i> should additionally be included as a candidate gene for unexplained cases of human NAD.