RT Journal Article SR Electronic T1 Sensory neuron fate is developmentally perturbed by Gars mutations causing human neuropathy JF bioRxiv FD Cold Spring Harbor Laboratory SP 071159 DO 10.1101/071159 A1 James N. Sleigh A1 John M. Dawes A1 Steven J. West A1 Emily L. Spaulding A1 Adriana Gómez-Martín A1 Robert W. Burgess A1 M. Zameel Cader A1 Kevin Talbot A1 David L. Bennett A1 Giampietro Schiavo YR 2016 UL http://biorxiv.org/content/early/2016/08/25/071159.abstract AB Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system in CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behaviour concordant with the afferent imbalance, which is present at birth and non-progressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. This suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.Significance Statement Charcot-Marie-Tooth disease (CMT) is a collection of genetically diverse inherited nerve disorders with the unifying feature of peripheral neuron degeneration. The mechanisms triggering this motor and sensory nerve dysfunction 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 mechanisms leading to afferent deterioration, we have studied the sensory nervous system of CMT Type 2D mice. Our work indicates that the specific cellular identity of sensory nerves is perturbed in mutant mice pre-natally. CMT therefore manifests through the complex interplay between malfunctioning developmental, maturation, and survival programs, which has important ramifications for therapeutic timing.