Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations

Significance The mechanisms triggering motor and sensory nerve dysfunction in the genetically diverse Charcot–Marie–Tooth disease (CMT) remain unresolved, as does the reason for the lack of sensory pathology observed in distal hereditary motor neuropathies, which can be associated with CMT genes. To unravel the pathways leading to afferent deterioration, we have studied the sensory nervous system of CMT type 2D (CMT2D) mice. Our work demonstrates that the specific cellular identity of sensory nerves is perturbed in mutant mice prenatally, and that this is likely caused by aberrant interaction of mutant CMT2D protein with Trk receptors impacting their prodifferentiation/development signaling. CMT therefore manifests through malfunctioning of the complex interplay between developmental, maturation, and survival programs, which has important implications for therapeutic timing.