Dataset Information

A Missense Mutation in the Vacuolar Protein Sorting 11 (VPS11) 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 (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.

SUBMITTER: Lucot KL

PROVIDER: S-EPMC6071611 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Lucot Katherine L KL Dickinson Peter J PJ Finno Carrie J CJ Mansour Tamer A TA Letko Anna A Minor Katherine M KM Mickelson James R JR Drögemüller Cord C Brown C Titus CT Bannasch Danika L DL

G3 (Bethesda, Md.) 20180731 8

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 ( ...[more]

PMID: 29945969

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Project description:Clinical, pathological and genetic examination revealed an as yet uncharacterized juvenile-onset neuroaxonal dystrophy (NAD) in Spanish water dogs. Affected dogs presented with various neurological deficits including gait abnormalities and behavioral deficits. Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord. Iron accumulation was absent. Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry. The family history of the four affected dogs suggested an autosomal recessive inheritance. SNP genotyping showed a single genomic region of extended homozygosity of 4.5 Mb in the four cases on CFA 8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. By whole genome re-sequencing of one affected dog, a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W). This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP). In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways. Furthermore, the canine NAD form reveals similarities to cases of human NAD defined by widespread spheroid formation without iron accumulation in the basal ganglia. Thus TECPR2 should also be considered as candidate gene for human NAD. Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways. Consequently, this report provides the first genetic characterization of juvenile canine NAD, describes the histopathological features associated with the TECPR2 mutation and provides evidence to emphasize the association between failure of autophagy and neurodegeneration.

Dataset Information

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

Publications

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

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