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Publication

Deciphering the pathology of PP2A-related intellectual disability

Book - Dissertation

PP2A-related intellectual disability (ID) is a recently discovered syndrome, characterized by neurodevelopmental delay and various comorbidities. Thus far, causal mutations have been identified in the structural Aα and regulatory B56δ, -β and -γ subunits. In this thesis, we report 16 individuals with mutations in the catalytic Cα subunit, resulting in ID, often accompanied by seizures, behavioral problems and brain malformations. Biochemical analysis revealed divergent binding defects to both the structural A, and several regulatory B-type subunits. Some variants were thought to behave as dominant-negative to certain B-type holoenzymes, whereas others induced haploinsuffiency, often associated with a milder phenotype. In parallel, newly identified variants in the B56δ subunit were biochemically characterized and found to frequently induce binding deficiencies towards the PP2A core dimer, being the catalytic C and structural A subunits. Moreover, a set of selected B56δ variants showed significantly reduced interaction with several substrates, such as liprin-α1 and -α3, PRR14 and PRR14L, and phosphorylation of the Ser573 residue appeared to be dysregulated for four out of six tested B56δ mutations, suggesting a potential downstream effect on signaling. However, besides a, possibly artificial, inability to stabilize ERK Thr185/Tyr187 phosphorylation in an overexpression set-up and an induction of the mTOR pathway for the p.E420K variant, no general signaling defect could be clearly linked to these B56δ mutations. Finally, a mouse model heterozygously expressing the most common variant, B56δ p.E198K, was significantly smaller than its wild type counterpart, with no measurable effects on brain size. Furthermore, preliminary analysis using embryonic stem cells generated from this model showed a delayed cortical development. Together, these data provide substantial insight in PP2A-related ID's pathology, imperative in the further deciphering of causal mechanisms in light of potential therapeutic opportunities.
Publication year:2021
Accessibility:Embargoed