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. 15 DM-affected and 31 unaffected PWC homozygous for SOD1 mutation genotyped using the Illumina CanineHD array (~170,000 SNPs genomewide)
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. 15 DM-affected and 10 unaffected Boxers homozygous for SOD1 mutation genotyped using the Illumina CanineHD array (~170,000 SNPs genomewide)
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.
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.
Project description:Boxer dataset for genome-wide association study of modifiers of risk of canine degenerative myelopathy in dogs homozygous for SOD1 mutation
Project description:PWC dataset for genome-wide association study of modifiers of risk of canine degenerative myelopathy in dogs homozygous for SOD1 mutation
Project description:A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.
Project description:Amyotrophic lateral sclerosis and primary lateral sclerosis are two syndromic variants within the motor neurone disease spectrum. Whilst primary lateral sclerosis is associated with loss of upper motor neurons and a more benign disease course up to 17yrs, amyotrophic lateral sclerosis is caused by loss of both upper and lower motor neurons and has an average disease course of 2-3 years. The majority of cases are sporadic, thereby limiting the availability of cellular models for investigating pathogenic disease mechanisms. The aim of the present study was to evaluate fibroblasts as a cellular model for sporadic amyotrophic lateral sclerosis and primary lateral sclerosis, to establish whether disease-related dysregulated biological processes recapitulate those seen in the central nervous system and to elucidate pathways that distinguish between the two disease phenotypes. We used microarray analysis to determine the differences in gene expression between fibroblasts derived from skin biopsies taken from sporadic amyotrophic lateral sclerosis and primary lateral sclerosis neurologically normal human controls