The animals exhibit an unsteady gait, with 'high' hind limbs (walking on hind toes), which can be observed at approximately 4 weeks of age (mean 4.6+/-0.7; n=21, but as early as 3 weeks of age); the impairment progresses over time, i.e. hind limbs become weaker, and the animals show a staggering gait. Because of phenotypic similarities to nmf291, allele tests between nmf205 and nmf291 were performed but did not produce any affected mice.
Standard pathology work-up on four mutants (38 to 51 days of age) revealed loss of cerebellar granule cells in all four animals and cortical laminar necrosis in three animals. Subsequent characterization by Ishimura et al, 2014, revealed that the nmf205 mutation in Gtpbp2 requires the presence of the n-Tr20m1J point mutation, a strain characteristic of C57BL/6J and C57BL/6JEiJ, in order for the neurodegenerative phenotype to present. The phenotype results from ribosomal stalling at AGA codons, which requires the presence of both mutations for full phenotypic expression. The phenotypic assessment was further characterized and found to include neurodegeneration in the retina including photoreceptor degeneration, and degeneration of amacrine, horizontal, and ganglion cells. Mice die by 8 to 9 weeks of age with progressive neuronal apoptosis. Apoptotic loss is found between 3 and 4 weeks of age the inner granule layer, and between 5 and 8 weeks of age also in the granule cells of the dentate gyrus, CA2 pyramidal neurons, and layer IV cortical neurons.
