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

• Published in: G3 Genes|Genomes|Genetics
• Main Authors: Lucot, Katherine L, Dickinson, Peter J, Finno, Carrie J, Mansour, Tamer A, Letko, Anna, Minor, Katherine M, Mickelson, James R, Drögemüller, Cord, Brown, C Titus, Bannasch, Danika L
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press (OUP) 2018
• Subjects: Canis lupus
• Online Access: http://dx.doi.org/10.1534/g3.118.200376; http://academic.oup.com/g3journal/article-pdf/8/8/2773/37126070/g3journal2773.pdf

Abstract Canine neuroaxonal dystrophy (NAD) is a recessive, degenerative neurological disease of young adult Rottweiler dogs (Canis lupus familiaris) 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 (VPS11) 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%. VPS11 mutations have been associated with a degenerative leukoencephalopathy in humans, and VSP11 should additionally be included as a candidate gene for unexplained cases of human NAD.