Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

Abstract

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 × 10 −5), and was associated with increased probability of developing DM (P = 4.8 × 10 −6 ) and earlier onset of disease (P = 1.7 × 10 −5 ). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.degenerative myelopathy | amyotrophic lateral sclerosis | ALS | SOD1 | SP110

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

“…Interestingly, ≥34 repeats in ATXN2 are associated with spinocerebellar ataxia (Sproviero et al, 2017). which is an analog of ALS in humans (Ivansson et al, 2016). Whether SP110 variants are risk modifiers in humans remains to be studied in the future.…”

“…Such genes include the paraoxonases ( PON1 , PON2 , PON3 ), the metallothioneins, and others (Dardiotis et al., ). Finally, variants in the SP110 gene have been shown to modify the risk of degenerative myelopathy in dogs, which is an analog of ALS in humans (Ivansson et al., ). Whether SP110 variants are risk modifiers in humans remains to be studied in the future.…”

Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs

“…The small sample size of our GWA analysis is likely to have hampered the statistical power of our study, as reflected by the magnitude of the association. However, the stringent phenotypic inclusion criteria used in this study may counterbalance the small sample size, the resulting level of association and its reliability, similarly to previous studies mapping canine complex traits [4,33]. Moreover, the small sample size of our study population may have contributed to the unexpectedly long associated locus reported here.…”

Species‐specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1)

“…4,5 A protein's ability to cause disease can solely rest with expression of the mutant protein (complete penetrance) or its pathogenesis can be modified by other genetic or environmental factors. 7 This means that dog E40K mutant SOD1, and other genetic variants contribute to the DM phenotype. 7 This means that dog E40K mutant SOD1, and other genetic variants contribute to the DM phenotype.…”