Imbalance between RNA-binding proteins and the WAVE regulatory complex underlies the toxic gain-of-function effects of the CYFIP2 Arg87Cys variant in neurodevelopmental disorders

In Cyfip2+/R87C mice, an imbalance between CYFIP2-associated RBP networks and WRC components is linked to early CA1 pyramidal neuron layer dispersion, with deeper-layer neurons most affected.

• Why it matters: CYFIP2 Arg87 hotspot variants produce unusually severe neurodevelopmental phenotypes, but it was unclear how CYFIP2’s RNA-regulatory and actin/WAVE-complex roles combine to produce toxic gain-of-function effects.
• What they did: At postnatal week 7, the study used single-nucleus RNA-seq, quantitative proteomics, and phosphoproteomics in CA1, plus 293T cell expression of CYFIP2 Arg87Cys and electrophysiology with biocytin morphology in CA1 neurons.
• The result: Proteomics showed increased RBP-associated proteins with reduced WRC components, phosphoproteomics altered synaptic and translational regulators, and recordings/morphology revealed more miniature excitatory postsynaptic currents and dendritic changes, alongside reduced Eph receptor A3.

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