A recessive Trim2 mutation causes an axonal neuropathy in mice.

We analyzed Trim2 mice, generated by CRISPR-Cas9, which have a recessive, null mutation of Trim2. Trim2 mice develop ataxia that is associated with a severe loss of cerebellar Purkinje cells and a peripheral neuropathy. Myelinated axons in the CNS, including those in the deep cerebellar nuclei, have focal enlargements that contain mitochondria and neurofilaments. In the PNS, there is a loss of myelinated axons, particularly in the most distal nerves. The pathologically affected neuronal populations - primary sensory and motor neurons as well as cerebellar Purkinje cells - express TRIM2, suggesting that loss of TRIM2 in these neurons results in cell autonomous effects on their axons. In contrast, these pathological findings were not found in a second strain of Trim2 mutant mice (Trim2), which has a partial deletion in the RING domain that is needed for ubiquitin ligase activity. Both the Trim2and the Trim2 alleles encode mutant TRIM2 proteins with reduced ubiquitination activity. In sum, Trim2 mice are a genetically authentic animal model of a recessive axonal neuropathy of humans, apparently for a function that does not depend on the ubiquitin ligase activity.