Identification of a novel CLPX variant in a mixed breed dog with anemia and spinocerebellar ataxia

Spinocerebellar ataxia (SCA) or hereditary ataxia is a progressive neurodegenerative disorder primarily manifesting as cerebellar or spinocerebellar dysfunction, resulting in the loss of motor control and voluntary muscle coordination. SCAs are typically inherited conditions, with causative genetic variants identified in multiple genes in people and across various dog breeds. Recently, an atypical case of SCA was documented in a mixed breed dog. In addition to the classic clinical signs and spinocerebellar lesions of SCA, the dog had retinal and optic nerve degeneration and severe, non-regenerative anemia. Whole-genome sequence (WGS) of the affected dog did not reveal any previously identified canine SCA-associated variants. Subsequent variant filtering against a control cohort of over 700 unaffected dog genomes identified a homozygous 4-base-pair frameshift deletion in caseinolytic mitochondrial matrix peptidase chaperone subunit X (CLPX) [XM_038580726.1:c.1723_1726del]. CLPX encodes a subunit of the ATP-dependent ClpXP protease, a molecular chaperone involved in mitochondrial protein degradation. The variant is predicted to cause a frameshift and a premature stop codon within 17 amino acids, truncating approximately 6.64% of the protein. Our study is the first to explore the association of CLPX variants with SCA in any species. Given the high evolutionary conservation of CLPX, this report of a CLPX variant associated with SCA in a dog may have relevance for understanding CLPX-related neurodegeneration and/or anemia in other species.