Australian Working Kelpie (WGS)

Cerebellar Abiotrophy in Australian Working Kelpies is affected by two major risk variants Claire M. Wade1?*, Annie Y.H. Pan2?, Mark Krockenberger2, Rosanne M. Taylor2, Peter Williamson1 E-mail: [e-mail] (CW) Abstract An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterised by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, wide-based stance, and high-stepping gait. A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two loci, one on CFA9 and a second on CFA20 that are significantly associated with CA in this breed. Investigation of clinical and pathological features of completely phenotyped affected dogs indicates that those homozygous for the risk haplotype on CFA20 (23 dogs) show clinical signs before ten weeks of age. Histopathology shows Purkinje cell loss, and a reduced molecular layer of the cerebellum. Missense variants in the sixth exon of disruptor of telomeric silencing 1-like (DOT1Lp.R200Q) and in the only exon of Leucine Rich Repeat And Ig Domain Containing 3 (LINGO3p.R359C) segregate with the associated risk haplotype on CFA20 that segregates with incomplete penetrance (42%). Not all animals with the CFA20 risk haplotype have the DOT1L variant. Affected dogs that are homozygous for the risk haplotype on CFA9 have later onset of progressive ataxia. Their histopathology shows axonal spheroids in white matter tracts of the cerebellum and Purkinje cell loss. A missense variant in exon 5 of Vacuole Membrane Protein 1 (VMP1 p.P160Q) segregates as a fully penetrant Mendelian recessive with the later-onset CA phenotype. Across mammals, the variety of causative loci so far identified as influencing cerebellar disorders reinforces the complexity of the pathways that contribute to cerebellar development and function, and to the pathophysiological mechanisms that may lead to cerebellar ataxia.