In addition to the tRNA processing defects described here, the combined effect of the CLP1 loss-of-function phenotypes may be due to impaired phosphorylation of target RNA. In particular, CLP1 functions as an siRNA kinase required for loading siRNA onto the RISC complex (Weitzer and Martinez, 2007), and thus there may be other cellular effects on these pathways as a result of the mutation. CLP1 also functions as part of a multi-protein complex required for 3’-end cleavage in pre-mRNA processing and maturation (de Vries et al., 2000; Wickens and Gonzalez, 2004), and not surprisingly we observed CLP1R140H-bound protein complexes were depleted of mRNA 3’-end processing proteins (data not shown). Further experimentation will be required to test whether these other cellular mechanisms contribute to the disease pathogenesis in these patients.
