Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 147450 , 618598

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2021

Inheritance: Mandigers et al. (2021): "Pedigree analysis indicated autosomal recessive inheritance."

Mapping: Mandigers et al. (2021): "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 top SNPs were located between positions 25.1–25.2 Mbp of CFA31 (CanFam3.1)"

Molecular basis: Mandigers et al. (2021): "The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. ... A G-nucleotide of the fourth codon of the gene is replaced by a CAC-trinucleotide. The shifted coding sequence runs into a stop codon at the tenth codon. The annotation of the indel mutation is NM001003035.1:c.12delinsCAC. The protein annotation is NP_001003035.1:p.Lys4Aspfs*6. The genomic annotation cannot be given because exon 1 of SOD1 is not represented in the reference genome CanFam3.1. ... None of the other analyzed dogs of the breed was homozygous for the mutation ..."

Clinical features: Mandigers et al. (2021): "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. ... In all pups, routine hematology and clinical chemistry and urinalysis did not reveal any significant abnormalities. In two pups the complete vertebral column was radiographically examined, in four pups an EMG (electromyogram) performed and these did not reveal any abnormalities. On four pups a so-called tensilon test was performed that ruled out myasthenia gravis. In two pups the acetylcholinesterase receptor titer for myasthenia gravis was measured and was found not to be abnormal. In seven pups titers for toxoplasmosis and neospora revealed no increase. In three pups an additional organic acid analysis was performed, which did not reveal any abnormality."

Pathology: Mandigers et al. (2021): "Routine post-mortem examinations were possible in 8 of these 12 pups. These revealed no morphological abnormalities macroscopically. Histologically, the most consistent finding was mild, random Wallerian-like degeneration in the brain stem and spinal cord with mild denervation atrophy of the skeletal muscle."

Breed: Markiesje.

Associated gene: