Paper

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

Coffey, Madeline C., Kim, Namju J., Johnston, Andrea, Blake, Jeanna M., Miller, Andrew D., Lee, Jeongha, de Cecco, Bianca S., Ekenstedt, Kari J.

2025

Overview

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. A young mixed-breed dog developed a gait abnormality that progressively worsened, together with vision loss, and severe anemia. Despite treatment, the dog’s condition deteriorated, and he was humanely euthanized. An autopsy revealed extensive abnormalities in the brain, spinal cord, eyes, and bone marrow. These histologic findings supported a diagnosis of spinocerebellar ataxia (SCA), also known as hereditary ataxia, which is a genetic neurological disorder that results in impaired movement and diminished coordination. Genetic analysis identified a previously unreported mutation in the CLPX gene. CLPX plays a key role in mitochondrial protein quality control by helping break down damaged or misfolded proteins within mitochondria—cell structures critical for energy production that are particularly crucial in high-demand tissues like the brain. This mutation likely disrupted normal CLPX protein function, leading to both nerve damage and impaired blood cell production. While related genes are known to cause similar conditions in humans, this is the first time a naturally occurring CLPX variant has been identified in an SCA case in any species. Because CLPX is highly conserved between dogs and humans, this finding may offer valuable insights into rare inherited neurological diseases in people.

• Publisher: Cold Spring Harbor Laboratory
• Subject: Genomics