title: 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.
authors.affiliation: 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.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Ivansson
authors.affiliation: 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;
authors.forename: Kate
authors.identifier: 0000-0002-1458-0865
authors.initials: K
authors.lastname: Megquier
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden;
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Kozyrev
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 751 23 Uppsala, Sweden;
authors.forename: Eva
authors.initials: E
authors.lastname: Murén
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden;
authors.forename: Izabella Baranowska
authors.initials: IB
authors.lastname: Körberg
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
authors.forename: Ross
authors.initials: R
authors.lastname: Swofford
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142;
authors.forename: Michele
authors.initials: M
authors.lastname: Koltookian
authors.affiliation: 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;
authors.forename: Noriko
authors.initials: N
authors.lastname: Tonomura
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
authors.forename: Ana L
authors.initials: AL
authors.lastname: Kolicheski
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
authors.forename: Liz
authors.initials: L
authors.lastname: Hansen
authors.affiliation: Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO 65201;
authors.forename: Martin L
authors.initials: ML
authors.lastname: Katz
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
authors.forename: Gayle C
authors.initials: GC
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211;
authors.forename: Gary S
authors.initials: GS
authors.lastname: Johnson
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri, Columbia, MO 65211.
authors.forename: Joan R
authors.initials: JR
authors.lastname: Coates
authors.affiliation: 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.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
mesh_terms: D017668:Age of Onset; D000818:Animals; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005260:Female; D055106:Genome-Wide Association Study; D006720:Homozygote; D008297:Male; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013118:Spinal Cord Diseases / Q000235:genetics* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D013482:Superoxide Dismutase
keywords: ALS; SOD1; SP110; amyotrophic lateral sclerosis; degenerative myelopathy