4.6 Article

A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy

Journal

HUMAN GENETICS
Volume 140, Issue 11, Pages 1547-1552

Publisher

SPRINGER
DOI: 10.1007/s00439-021-02271-6

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Funding

  1. Dutch breed club `Nederlandse Markiesjes Vereniging'

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A juvenile form of paroxysmal dyskinesia was identified in the Markiesje dog breed, with a frameshift mutation in the SOD1 gene being the underlying cause. The mutation showed full penetrance in affected dogs but was not found in other analyzed dogs of the breed. This genetic defect leads to a distinct juvenile neurologic disease, different from the related diseases seen in humans and other dog breeds.
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.

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