title: TECPR2 Associated Neuroaxonal Dystrophy in Spanish Water Dogs.
abstract: 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.
authors.affiliation: University of Veterinary Medicine Hannover, Department of Pathology, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hahn
authors.affiliation: University Animal Hospital, Swedish University of Agricultural Sciences, Uppsala, Sweden.|Anicura, Albano Small Animal Hospital, Danderyd, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rohdin
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: University of Veterinary Medicine Hannover, Department of Pathology, Hannover, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Wohlsein
authors.affiliation: University of Veterinary Medicine Hannover, Department of Pathology, Hannover, Germany.|Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: University of Veterinary Medicine Hannover, Department of Pathology, Hannover, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Seehusen
authors.affiliation: University of Veterinary Medicine Hannover, Department of Pathology, Hannover, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Spitzbarth
authors.affiliation: Department of Biomedical Sciences and Veterinary Public Health, Division of Pathology, Pharmacology and Toxicology, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Grandon
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Department of Companion Animal Clinical Sciences, Norwegian University of Life Sciences, Oslo, Norway.
authors.forename: Karin Hultin
authors.initials: KH
authors.lastname: Jäderlund
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping; D017124:Conserved Sequence; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs / Q000145:classification / Q000235:genetics*; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006801:Humans; D008126:Lod Score; D008322:Mammals / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D006211:Pantothenate Kinase-Associated Neurodegeneration / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics; D013045:Species Specificity; D013116:Spinal Cord / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C578280:TECPR2 protein, human