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Proc Natl Acad Sci U S A. 2016 May 31;113(22):E3091-100. doi: 10.1073/pnas.1600084113. Epub 2016 May 16.

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

Author information

1
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; emma.ivansson@ki.se kersli@broadinstitute.org.
2
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
3
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden;
4
Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden;
5
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
6
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA 01536;
7
Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
8
Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65201;
9
Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211.

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.

KEYWORDS:

ALS; SOD1; SP110; amyotrophic lateral sclerosis; degenerative myelopathy

PMID:
27185954
PMCID:
PMC4896683
DOI:
10.1073/pnas.1600084113
[Indexed for MEDLINE]
Free PMC Article

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