Summary: Researchers have identified a modifier gene that affects the risk of developing degenerative myelopathy, a canine disease similar to ALS in Welsh corgis.
Source: Uppsala University.
Canine Degenerative Myelopathy (DM) is a neurodegenerative disease in dogs with similarities to ALS in humans. Scientists at Uppsala University, SciLifeLab and the Broad Institute of MIT and Harvard, in collaboration with researchers at the University of Missouri, have discovered a modifier gene that affects the risk of developing DM in Pembroke Welsh Corgis (PWC). The study is published in PNAS this week.
Degenerative Myelopathy is a naturally occurring, progressive adult onset disorder of the spinal cord that leads to paralysis and death. In 2009, a SOD1 mutation was associated with risk of developing the disease. However, not all dogs with the mutation became affected, prompting the hypothesis that additional genes could modify disease risk.
Genome-wide association analysis comparing affected and unaffected PWC with the SOD1 mutation identified a haplotype within the gene ‘SP110 nuclear body protein’ that was associated with increased risk of developing DM and early age of onset.
“We discovered several variants in SP110 that were more common in the PWCs that developed DM” says Emma Ivansson, former PostDoc at Uppsala University leading the study.
“Our functional studies revealed that the variants alter expression of SP110 in blood cells” continues Sergey Kozyrev, senior scientist at Uppsala University.
“Whether SP110 affects the risk of DM also in other dog breeds requires further investigation”, says Kate Megquier, veterinarian and PhD student at Uppsala University and Broad Institute.
SP110 is a regulator of gene expression, mainly in immune cells. It is known that the immune response is important in neurodegeneration, but inflammation can be either protective or damaging and the exact mechanisms are still unclear.
“Many studies have investigated the role of immunity in ALS, and our finding that a gene regulating the immune response is important in this canine model of ALS could provide a new angle” says Emma Ivansson.
Funding: The project was supported, in part, by grants from the American Kennel Club Canine Health Foundation (Grants 01271A, 01212A, and 01213A), the ALS Association (Grant 48892), the Swedish Research Council, and the Swedish Research Council Formas. E.L.I was supported by postdoctoral grants from the Swedish Society for Medical Research and Swedish Childhood Cancer Foundation. K.L.-T. was supported by a European Young Investigator Award from the European Science Foundation as well as a Consolidator Award from the European Research Council.
Source: Kate Megquier – Uppsala University Image Source: This NeuroscienceNews.com image is credited to Emw and is licensed CC BY-SA 3.0. Original Research: Full open access research for “Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy” by Emma L. Ivansson, Kate Megquier, Sergey V. Kozyrev, Eva Murén, Izabella Baranowska Körberg, Ross Swofford, Michele Koltookian, Noriko Tonomura, Rong Zeng, Ana L. Kolicheski, Liz Hansen, Martin L. Katz, Gayle C. Johnson, Gary S. Johnson, Joan R. Coates, and Kerstin Lindblad-Toh in PNAS. Published online May 16 2016 doi:10.1073/pnas.1600084113
[cbtabs][cbtab title=”MLA”]Uppsala University. “Second Gene Modifies Effect of Mutation in a Dog Model of ALS.” NeuroscienceNews. NeuroscienceNews, 16 May 2016. <https://neurosciencenews.com/sod1-als-sp110-4232/>.[/cbtab][cbtab title=”APA”]Uppsala University. (2016, May 16). Second Gene Modifies Effect of Mutation in a Dog Model of ALS. NeuroscienceNews. Retrieved May 16, 2016 from https://neurosciencenews.com/sod1-als-sp110-4232/[/cbtab][cbtab title=”Chicago”]Uppsala University. “Second Gene Modifies Effect of Mutation in a Dog Model of ALS.” NeuroscienceNews. https://neurosciencenews.com/sod1-als-sp110-4232/ (accessed May 16, 2016).[/cbtab][/cbtabs]
Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy
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.
“Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy” by Emma L. Ivansson, Kate Megquier, Sergey V. Kozyrev, Eva Murén, Izabella Baranowska Körberg, Ross Swofford, Michele Koltookian, Noriko Tonomura, Rong Zeng, Ana L. Kolicheski, Liz Hansen, Martin L. Katz, Gayle C. Johnson, Gary S. Johnson, Joan R. Coates, and Kerstin Lindblad-Toh in PNAS. Published online May 16 2016 doi:10.1073/pnas.1600084113