Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601825 (gene) , 256000 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2024

Molecular basis: Christen et al. (2024): "Whole genome sequencing [of an affected Jack-Russell Terrier × Chihuahua cross] identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G>A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. [The authors] investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20." Knockdown of ND-20 leads to a lethal phenotype, in which developing flies arrest at the dark pupae stage. Expression of the canine wildtype protein resulted in a partial rescue, while expression of the canine mutant protein led to an even earlier developmental arrest than in the knockdown line.  

Clinical features: Christen et al. (2024): "Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels." Disease onset was at ~4 months of age and the two dogs were euthanized at ~6 months of age due to the severity of their clinical phenotype.

Pathology: Christen et al. (2024): "Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia." Muscle histopathology revealed variability in myofiber size and some accumulations of mitochondria. Ragged red fibers were not obvious.

Breed: Mixed Breed (Dog) (VBO_0200902).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: