An Investigation into the Molecular Genetics and Pathology of Cerebellar Abiotrophy in Australian Working Kelpie Dogs

Australian working Kelpie dogs are affected with an autosomal recessive form of cerebellar ataxia (cerebellar abiotrophy, CA) that is characterised by a degeneration of neurons in the cerebellar cortex. The clinical signs of CA include cerebellar ataxia and head tremor etc., with a clinical onset of 4 to 16 weeks old (early-onset), however a later age of onset for some dogs (later-onset) is reported in this study. Degeneration of Purkinje cells and granule cells, and activation of astrocytes were present throughout the cerebellum of all early-onset and later-onset CA affected working Kelpie dogs. Axonal spheroids were found to be present in the cerebellar white matter of later-onset CA affected working Kelpies. Multi-dimensional scaling analysis using PLINK software revealed 3 separate clusters of individuals: working type Kelpies, a single extended family of working type Kelpies with CA affected members from Germany, and non-working type Kelpies. In order to account for the population stratification and the different pathology pattern observed in affected dogs, 3 separate genome-wide association studies were performed. Homozygosity analysis and whole genome sequencing identified an intronic deletion in the NUP153 gene that segregated with the phenotype in the working Kelpie family from Germany, and a deleterious mutation in VMP1 for the later-onset CA affected working Kelpies. The whole genome sequencing approach failed to identify a causal DNA variant for CA in the early-onset CA affected working Kelpies, however 2 risk haplotypes were identified from the association analysis. The results of this study have contributed to our understanding of the pathophysiology and molecular genetics of CA in working Kelpies. This study has provided an avenue for informed management practices for working Kelpie breeders via genetic testing