Integrated, multimodal phenotypic analysis of Ppp2r1a knockin mice: new in vivo models of syndromic PP2A-related (neuro)developmental disorders.
De novo, recurrent mutations in PPP2R1A, encoding the scaffolding Aα subunit of Protein Phosphatase 2A (PP2A), were recently identified among the new genetic causes of intellectual disability (ID) and (neuro)developmental delay (NDD). Two biochemically and clinically distinguishable subgroups were determined. One group of variants (exemplified by M180T) caused a milder phenotype (moderate ID, no seizures, macrocephaly tendency, absent in tumors), while the other group (exemplified by R182W) caused a more severe phenotype (severe ID, seizures, microcephaly tendency, somatic occurrence in tumors). Although the biochemical characterization of these variants could rationalize these severity differences, the molecular basis for their differential effect on organismal and brain function remains unknown. Here, we designed heterozygous Ppp2r1a M180T/+ and R182W/+ knockin mice to model the pathogenesis of mild and severe PPP2R1A-related NDD. We aim to extensively phenotype both models using a multimodal approach, integrated at the organism, tissue, cell and molecular level, focusing on neonatal, adult and epileptic behavior, potential age-related phenotypes (neurodegeneration and cancer), in vivo imaging, analysis of neuronal and synaptic biology, and brain transcriptomics and (phospho)proteomics. The integrative analysis of these data will increase our basic understanding of these new, complex genetic disorders, which is vital for disease management and potential treatment.