Authors:

Namju Kim

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About Paper:

Spinocerebellar ataxia (SCA) is a progressive neurodegenerative disorder primarily affecting the cerebellum, resulting in the loss of motor control and voluntary muscle coordination. While previously described in Jack and Parson Russell Terriers due to autosomal recessive mutations in the genes CAPN1 and KCNJ10, and in other dog breeds in SCN8A, SLC12A6, and SPTBN2 (Alpine Dachsbracke, Belgian Malinois, and Beagle, respectively), an atypical case of SCA was recently documented in a mixed breed dog. Health records and necropsy findings identified paraparesis, SCA, anemia, and retinal degeneration in this individual. Because SCAs are inherited conditions, whole-genome sequence (WGS) was generated for the affected dog, with the aim of identifying the underlying genetic mutation driving the phenotype. The known canine mutations above were not present in this affected mixed-breed dog. Principal Component Analysis of genomic data confirmed this dog's mixed-breed identity. The affected dog's WGS was then screened for private variants compared to WGS from >700 unaffected dogs. This established variant elimination pipeline revealed a private homozygous exonic 4-base-pair mutation in CLPX. CLPX is a novel candidate gene for SCA in any species that encodes a subunit of a molecular chaperone involved in mitochondrial protein degradation in a pathway related to SCA. In-silico tools predict a frameshift and a premature stop codon within 17 amino acids, truncating 6.64% of the protein. Our study is the first to explore the association of CLPX mutation with SCA. This connection is potentially significant for human health due to the high evolutionary conservation of CLPX across species. Keywords: Neurodegenerative Disease; Genetics; Canine; Mitochondria; clpx

Source:

Purdue University / 2024

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Co-authors:

Namju Kim