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PWC dataset for genome-wide association study of modifiers of risk of canine degenerative myelopathy in dogs homozygous for SOD1 mutation

ABSTRACT: Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM is a promising model for ALS, as genome-wide association identified a mutation in SOD1, a known ALS gene. In this study, we identify a modifier gene, SP110, which strongly affects overall disease risk and age-of-onset in Pembroke Welsh corgis at risk of DM. Dissecting the complex genetics of this disease in a model organism may lead to new insights about risk and progression in both canine and human patients.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE80735 | GEO | 2016/06/01

SECONDARY ACCESSION(S): PRJNA319840

REPOSITORIES: GEO

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Boxer dataset for genome-wide association study of modifiers of risk of canine degenerative myelopathy in dogs homozygous for SOD1 mutation

Project description:Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM is a promising model for ALS, as genome-wide association identified a mutation in SOD1, a known ALS gene. In this study, we identify a modifier gene, SP110, which strongly affects overall disease risk and age-of-onset in Pembroke Welsh corgis at risk of DM. Dissecting the complex genetics of this disease in a model organism may lead to new insights about risk and progression in both canine and human patients.

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Novel Blood-Based RNA Profiles can Predict Human Degenerative Cervical Myelopathy

Project description:In this study, we aim to identify and explore the diagnostic value of differentially expressed genes (DEGs) in the blood of patients with degenerative cervical myelopathy (DCM), cervical spondylotic radiculopathy (CSR), and healthy controls (HC).

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Canis lupus breed:Pembroke Welsh Corgis

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Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy.

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Novel Blood-Based RNA Profiles can Predict Human Degenerative Cervical Myelopathy

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Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis.

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Intrinsic structural vulnerability in the hydrophobic core induces species-specific aggregation of canine SOD1 with degenerative myelopathy-linked E40K mutation.

Project description:Canine degenerative myelopathy (DM), a fatal neurodegenerative disease in dogs, shares clinical and genetic features with amyotrophic lateral sclerosis, a human motor neuron disease. Mutations in the SOD1 gene encoding Cu/Zn superoxide dismutase (SOD1) cause canine DM and a subset of inherited human amyotrophic lateral sclerosis. The most frequent DM causative mutation is homozygous E40K mutation, which induces the aggregation of canine SOD1 but not of human SOD1. However, the mechanism through which canine E40K mutation induces species-specific aggregation of SOD1 remains unknown. By screening human/canine chimeric SOD1s, we identified that the humanized mutation of the 117th residue (M117L), encoded by exon 4, significantly reduced aggregation propensity of canine SOD1E40K. Conversely, introducing a mutation of leucine 117 to methionine, a residue homologous to canine, promoted E40K-dependent aggregation in human SOD1. M117L mutation improved protein stability and reduced cytotoxicity of canine SOD1E40K. Furthermore, crystal structural analysis of canine SOD1 proteins revealed that M117L increased the packing within the hydrophobic core of the β-barrel structure, contributing to the increased protein stability. Our findings indicate that the structural vulnerability derived intrinsically from Met 117 in the hydrophobic core of the β-barrel structure induces E40K-dependent species-specific aggregation in canine SOD1.

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Molecular screening for the mutation associated with canine degenerative myelopathy (SOD1:c.118G > A) in German Shepherd dogs in Brazil.

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