A novel, rapidly progressive ataxia due to a spontaneous <i>Myo5a</i> mutation in mice impairs transport proteins and alters mitochondria

Spontaneous mouse mutants have helped define genetic contributions to many phenotypes. Here we report a spontaneous Novel Ataxic Phenotype in mice. Ataxia findings were evident at post-natal day 11 in NAP mice and rapidly worsened, resulting in preweaning lethality. Using genome sequencing and genome-wide mapping, we identified a 3' donor splice variant in exon 14 of Myo5a, encoding an actin-based motor protein. The variant in Myo5a (c.1752g>a) excises exon 14 and ablates MYO5A protein expression, which is implicated in intracellular transport and Griscelli syndrome type I in humans. NAP mice displayed expansion of PAX6-positive cells in the external granule layer of the cerebellum, and mass spectrometry analysis of cerebellar extracts uncovered differentially abundant proteins involved in short-range organelle transport, and specifically proteins implicated with early endosomes. Using cerebellar lysates and primary neurons, we provide evidence for an interaction between MYO5A and ANKFY1, a known effector for the endosomal protein, RAB5A. We also found neurons from NAP mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis. This allele provides new insight into Myo5a function in developmental neuropathology.