- Awarded: 2021
- Award Type: Pilot
- Award #: 877875
PPP2R5D is a high-confidence (category 1) autism spectrum disorder (ASD) risk gene and the 13th most significantly neurodevelopmental disorder-associated gene in the genome. PPP2R5D encodes B’delta (aka B56d), one of 12 regulatory subunits of protein phosphatase 2A (PP2A), a dominant serine/threonine phosphatase expressed in all eukaryotic cells. PP2A is an ASD hub protein because it directly or indirectly regulates (by dephosphorylation) a number of other high-confidence risk genes, including MTOR, CTNNB1 and FMR11.
PPP2R5D is by far the most frequently mutated neurodevelopmental disorders risk gene among those encoding PP2A subunits. Nearly all PPP2R5D mutations are de novo, recurrent charge-reversal mutations (e.g., Glu → Lys) and result in Jordan’s syndrome (JS, aka MRD35), an autosomal dominant condition associated with intellectual disability and ASD. Identified by whole-exome sequencing, JS is known to affect close to 200 individuals and has an estimated prevalence of 220,000 cases worldwide.
With prior support from Jordan’s Guardian Angels, a foundation dedicated to finding a cure for the disorder, Stefan Strack and colleagues generated constitutive, inducible and reversible mouse models of the most common PPP2R5D missense mutations that cause JS (E198K, E200K, E420K). Remarkably, preliminary data reveal that, even in their heterozygous state, Ppp2r5d-mutant mice recapitulate cardinal features of JS, including developmental delay, macrocephaly, cognitive impairment and spontaneous seizures. This contrasts with other ASD risk genes (e.g., SHANK3, CNTNAP2) for which mutation of both alleles of the murine genes is required to cause behaviors in mice approximating the human heterozygous disease state.
Heterozygous Ppp2r5d-mutant mice therefore represent a unique model system to interrogate the pathogenic role of PPP2R5D as an ASD hub gene, and the genetic reversibility of JS. The current project addresses the novel hypothesis that JS-causing mutations in PPP2R5D generate a “toxic” form of PP2A that targets the wrong substrates and/or is no longer appropriately regulated by cAMP/PKA, thus derailing normal brain development. This hypothesis will be addressed in Aim 1 of the project by defining “molecular signatures” of JS by orthogonal and unbiased omics approaches. Aims 2 and 3 query the reversibility of JS symptoms at different ages, both by genetic (using an innovative FLExed allele) and pharmacological approaches (using a cAMP modulator that has recently been shown to improve daily functions in adults with fragile X syndrome2).
Insights from the proposed work are expected to inform not only future treatments of JS but also other ASDs caused by genetic mutations.
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