Dosage sensitivity in Pumilio1-related phenotypes reflects distinct disease mechanisms

Abstract

The RNA-binding protein (RBP) Pumilio1 (PUM1) is associated with two distinct diseases: a late-onset ataxia and a neurodevelopmental syndrome. The ataxia patients retain 75% of normal PUM1 levels, the syndromic patients ~50%, but this seems inadequate to explain the difference in phenotypes. We hypothesized that mild disease results from dysregulation of PUM1 targets, whereas severe disease involves disruption of PUM1 complexes and deregulation of shared targets. We therefore developed a PUM1 interactome for the murine brain and found that PUM1 shares targets with several RBP interactors (PUM2, FMRP, AGO2, and RBFOX3). PUM1 haploinsufficiency destabilizes these RBPs to varying degrees by brain region and sex, and alters expression of their shared targets, but the milder disease-causing mutation affects only PUM1-specific targets. These data indicate that dosage-sensitive proteins can produce different phenotypes by different mechanisms, and that there may be more intimate cooperation among RBPs than expected.

Characterization of the regulation of APC/CFZR-1 in the germline of Caenorhabditis elegans

“…This possibility is especially relevant in multicellular organisms. Interestingly, a study searching for Pumilio interactors in the murine brain revealed APC/C complex subunits as the main functional category (Botta et al, 2022). Pumilio is a family of RNA-binding proteins that act upstream of developmental processes modulating protein expression in different cells.…”

“…interactor in silico (Supplementary data in (Kershner & Kimble, 2010) (Botta et al, 2022). The 3' UTR from fzr-1 has a canonical FBF binding site in the 3' UTR (TGTxxxAT).…”