Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology. Overall design: Induced pluripotent stem cells reprogrammed from primary fibroblasts of an affected PCH10 patient ("Affected", CLP1 R140H/R140H) and their unaffected parent ("Unaffected", CLP1 R140H/+) were differentiated into mature motor neurons using an established protocol (Markmiller et al., Cell, 2018). For total RNA sequencing, 3 Affected clonal replicates and 2 Unaffected clonal replicates were used; for Poly(A)-Click sequencing and tRNA sequencing, 2 Affected clonal replicates and 2 Unaffected clonal replicates were used.