A canine Tectonin Beta-Propeller Repeat-Containing Protein 2 (TECPR2) missense mutation– disturbances of the autophagic pathway associated with neuroaxonal dystrophy in Spanish water dogs

The occurrence of a previously unknown neuroaxonal dystrophy (NAD) has been noticed in Perro de Agua Español (Spanish water dogs). Clinically, affected dogs displayed weakness of the pelvic limbs and paraparesis as well ataxia, circling, reduced or absent tail waggling, incontinence, deficits in peripheral reflexes and visual disturbances. Histologically, spheroid formation disseminated within the grey and white matter of the CNS, including cerebral hemispheres, cerebellum, brain stem, and spinal cord was found. The family history of four affected dogs suggested an autosomal recessive inheritance. High-density SNP genotyping detected a single genomic region of extended homozygosity of 4.5 Mb in four cases on CFA8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. The tectonin beta-propeller repeat-containing protein 2 (TECPR2) located at 70.3 Mb of CFA8 was identified as functional candidate gene for canine NAD. The phenotype of NAD affected dogs displays etiological, clinical, and histological parallels to one form of recessive inherited human hereditary spastic paraparesis caused by TECPR2 mutation. By whole genome re-sequencing of an affected Perro de Agua Español, a single non-synonymous coding sequence variant in canine TECPR2 gene (c.4009C>T or p.R1337W) was detected. This mutation was perfectly associated with the NAD disease of Perros de Agua Español and affects a highly conserved region of tectonin beta propeller repeat. TECPR2 protein participates in autophagic pathways interacting with LC3 and p62. Therefore, a possible influence in regard to autophagosome formation, clearance of aggregated protein complexes, removement of damaged mitochondria and endosomal transport deficits may be anticipated in the NAD of Perros de Agua Español. This study presents the first report of a naturally occurring TECPR2 mutation in animals associated with a neurodegenerative disease and underlines the importance of this protein and the autophagy pathway in the pathogenesis of neurodegenerative diseases.