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

Kim, U. S.; Jun, Y.; Kim, H.; Yang, Y.; Kang, M.; Ma, R.; Kang, H. R.; Ju, S.; Jeong, H.; Kim, S. Y.; Kim, Y.; Oh, J. Y.; Kim, E.; Kim, K.; Kang, H.; Kim, J. Y.; Han, K.

doi:10.64898/2026.10.27.762134

bioRxiv · 10.64898/2026.10.27.762134

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

Kim, U. S.·Jun, Y.·Kim, H.·Yang, Y.·Kang, M.·Ma, R.·Kang, H. R.·Ju, S.·Jeong, H.·Kim, S. Y.·Kim, Y.·Oh, J. Y.·Kim, E.·Kim, K.·Kang, H.·Kim, J. Y.·Han, K.

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Abstract

Pathogenic variants in cytoplasmic FMR1-interacting protein 2 (CYFIP2) cause neurodevelopmental disorders, with hotspot substitutions at arginine 87 (Arg87) associated with particularly severe symptoms. CYFIP2 functions both as a component of the WAVE (Wiskott-Aldrich syndrome protein family verprolin-homologous protein) regulatory complex (WRC), regulating the actin cytoskeleton, and as an interactor of RNA-binding proteins (RBPs) involved in mRNA processing/translation. Although Arg87 variants reduce CYFIP2 protein stability, heterozygous knock-in mice carrying Arg87Cys (Cyfip2+/R87C) show markedly more severe phenotypes than heterozygous knockout (Cyfip2+/-) mice, supporting a toxic gain-of-function mechanism. However, how the dual roles of CYFIP2 contribute to this mechanism remains unclear. To address this, we examined Cyfip2+/R87C mice at postnatal week 7, before overt neuronal loss and gliosis, focusing on the progressive dispersion of hippocampal cornu ammonis 1 (CA1) pyramidal neurons, a phenotype absent in Cyfip2+/- mice. Single-nucleus RNA sequencing suggested candidate alterations related to translation and cell adhesion/migration in CA1 pyramidal neurons. Complementarily, human embryonic kidney 293T cells expressing CYFIP2 Arg87Cys showed defects in proliferation and morphology, accompanied by altered expression of cell adhesion-related genes. Quantitative proteomic analysis of the CA1 region uncovered an imbalance between CYFIP2-associated protein networks, characterized by increased RBPs and reduced WRC components. Phosphoproteomic analysis further revealed altered phosphorylation of synaptic and translational regulators. Consistently, whole-cell recordings and biocytin-based morphological analyses showed increased frequency of miniature excitatory postsynaptic currents and altered dendritic morphology in Cyfip2+/R87C CA1 pyramidal neurons, most prominently in the more severely dispersed deep-layer neurons. Moreover, the cell adhesion molecule Eph receptor A3 was reduced, possibly as a result of RBP dysregulation. Together, these findings suggest that an imbalance between RBP- and WRC-associated pathways underlies the gain-of-function effects of CYFIP2 Arg87Cys and contributes to early neuronal phenotypes, most notably CA1 layer dispersion. This mechanism, distinct from CYFIP2 haploinsufficiency, supports allele-specific therapeutic strategies for Arg87 variants.

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Kim, U. S., Jun, Y., Kim, H., Yang, Y., Kang, M., Ma, R., Kang, H. R., Ju, S., Jeong, H., Kim, S. Y., Kim, Y., Oh, J. Y., Kim, E., Kim, K., Kang, H., Kim, J. Y., Han, K.. 2026-10-30. 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. https://doi.org/10.64898/2026.10.27.762134

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