Recent advances in CYFIP2-associated neurodevelopmental disorders: From human genetics to molecular mechanisms and mouse models

Abstract

Cytoplasmic FMR1-interacting protein 2 (CYFIP2) is an evolutionarily conserved protein with a critical role in brain development and function. As a key component of the WAVE regulatory complex, CYFIP2 regulates actin cytoskeleton dynamics, essential for maintaining proper neuronal morphology and circuit formation. Recent studies have also shown that CYFIP2 interacts with various RNA-binding proteins, suggesting its involvement in mRNA processing and translation in neurons. Since 2018, de novo CYFIP2 variants have been identified in patients with neurodevelopmental disorders, particularly developmental and epileptic encephalopathy and West syndrome, characterized by early-onset intractable seizures, intellectual disability, microcephaly, and developmental delay. This review summarizes these CYFIP2 variants and examines their potential impact on the molecular functions of CYFIP2, focusing on its roles in regulating actin dynamics and mRNA processing/translation. Additionally, we review various Cyfip2 mouse models, highlighting the insights they offer into CYFIP2 function, dysfunction, and clinical relevance. Finally, we discuss future research directions aimed at better understanding CYFIP2-associated neurodevelopmental disorders and potential therapeutic strategies.