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Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 22, p. E3091-E3100Article in journal (Refereed) Published
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Text
Abstract [en]

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 x 10(-5)), and was associated with increased probability of developing DM (P = 4.8 x 10(-6)) and earlier onset of disease (P = 1.7 x 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.

Place, publisher, year, edition, pages
2016. Vol. 113, no 22, p. E3091-E3100
Keywords [en]
degenerative myelopathy, amyotrophic lateral sclerosis, ALS, SOD1, SP110
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-298872DOI: 10.1073/pnas.1600084113ISI: 000376784600009PubMedID: 27185954OAI: oai:DiVA.org:uu-298872DiVA, id: diva2:948294
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2018-03-27Bibliographically approved
In thesis
1. Analysis of inherited and somatic variants to decipher canine complex traits
Open this publication in new window or tab >>Analysis of inherited and somatic variants to decipher canine complex traits
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents several investigations of the dog as a model for complex diseases, focusing on cancers and the effect of genetic risk factors on clinical presentation.

In Papers I and II, we performed genome-wide association studies (GWAS) to identify germline risk factors predisposing US golden retrievers to hemangiosarcoma (HSA) and B-cell lymphoma (BLSA). Paper I identified two loci predisposing to both HSA and BLSA, approximately 4 megabases (Mb) apart on chromosome 5. Carrying the risk haplotype at these loci was associated with separate changes in gene expression, both relating to T-cell activation and proliferation.

Paper II followed up on the HSA GWAS by performing a meta-analysis with additional cases and controls. This confirmed three previously reported GWAS loci for HSA and revealed three new loci, the most significant on chromosome 18. This locus contains several candidate genes with a clear role in carcinogenesis, including KMT5B and LRP5. Overall, carriers of the risk alleles at the top six loci are diagnosed with HSA earlier in life.

In Paper III we investigated the somatic mutations which occur in HSA tumor tissue by performing tumor-normal exome sequencing of 47 golden retrievers. We identified 7 recurrently mutated genes, including the tumor suppressor TP53 (mutated in 59.6% of tumors) and oncogene PIK3CA (mutated in 29.8% of tumors). Additional somatically mutated genes overlap those found in human angiosarcomas, suggesting that angiosarcomas in dogs and humans are genetically very similar.

In Paper IV, we investigated the variable penetrance of a SOD1 mutation in Pembroke Welsh corgis causing degenerative myelopathy (DM), a model of the human motor neuron disease amyotrophic lateral sclerosis (ALS). We discovered that regulatory variants near the SP110 gene were associated with an increased risk of DM and an earlier age at diagnosis, suggesting a role for immune response in the pathogenesis of the disease.

Taken together, these findings provide new insight into the pathophysiology of both hemangiosarcoma and degenerative myelopathy, which could guide future diagnostics and therapeutic strategies both in humans and veterinary patients. In addition, they demonstrate the power of the dog as a biomedical model for human complex diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 67
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1454
Keywords
dog, genetics, GWAS, exome, cancer, DM
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-347165 (URN)978-91-513-0310-9 (ISBN)
Public defence
2018-05-21, A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
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Available from: 2018-04-26 Created: 2018-03-27 Last updated: 2018-10-08

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Megquier, KateKozyrev, Sergey V.Murén, EvaLindblad-Toh, Kerstin

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