Two distinct mechanisms underlie dosage sensitivity in Pumilio1-associated diseases

The RNA-binding protein Pumilio1 (PUM1) is associated with distinct diseases: a mild, late-onset ataxia and a severe, wide-ranging neurodevelopmental syndrome. The ataxia patients retain 75% of normal PUM1 levels, the syndromic patients ~50%, but why this should cause such different phenotypes was unclear. Target dysregulation did not explain the difference, so we developed a PUM1 interactome for the mouse brain. This revealed RNA-binding proteins involved in aspects of RNA metabolism not previously associated with PUM1 (e.g., alternative splicing), as well as proteins in unexpected pathways (e.g., cyclosome). We focused on a subset of RNA-binding proteins and found that the effects of PUM1 loss on these proteins and their targets varied with brain region and sex. In patient cells, mice, and in vitro , mild PUM1 loss affected only PUM1-specific targets, whereas PUM1 haploinsufficiency destabilized these native complexes and altered expression of shared targets. We propose that dosage sensitivity can involve distinct mechanisms, and that there may be more intimate coordination among RNA-binding proteins than is readily evinced by more traditional in vitro approaches. Impact statement Most studies of RNA-binding proteins focus on identifying their targets, but identifying their protein partners in vivo provides important insights into their functions and loss of function. ### Competing Interest Statement The authors have declared no competing interest.