Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

AbstractMutations in the RNA-binding protein (RBP) Pumilio1 (PUM1) can cause dramatically different phenotypes. We previously noted that phenotypic severity tracked with protein dosage: a mild mutation that reduces PUM1 levels by 25% causes late-onset ataxia, whereas PUM1 haploinsufficiency causes developmental delay and seizures. Why this difference in expression should cause such different phenotypes has been unclear: PUM1 targets are de-repressed to equal degrees in both cases, and the more severe mutation does not hinder PUM1’s RNA-binding ability. We therefore developed a PUM1 interactome in the murine brain. We find that mild PUM1 loss de-represses PUM1-specific targets, but PUM1 haploinsufficiency disrupts several interactors and regulation of their targets. We validated these phenomena in patient-derived cell lines and show that normalizing PUM1 levels restores interactors and their targets to proper levels. We therefore propose that dosage sensitivity does not necessarily reflect a linear change in protein abundance but can involve distinct mechanisms. Studying the interactors of RBPs in vivo will be necessary to understand their functions in neurological diseases.