From amino acids to animal models: MAP2K2 mutations and their role in pathogenesis of CFC4 Syndrome

Abstract Background Cardio-facio-cutaneous syndrome type 4 (CFC4) is a rare RASopathy caused by germline mutations in the MAP2K2 gene, which encodes the MEK2 protein - a key kinase in the Ras/MAPK signaling pathway. Although the Ras/MAPK cascade has been widely studied due to its essential role in development and its implication in cancer biology, CFC4 remains one of the least characterized syndromes within the RASopathy spectrum. Pathogenic MAP2K2 variants have received limited attention in the literature so far, with most data derived from isolated case reports. Main body This review aims to synthesize current knowledge on MAP2K2 -related CFC4 with a particular emphasis on the molecular and functional consequences of mutations in this protein. We explore findings from in silico, in vitro, and translational studies, and highlight how particular mutations alter MEK2 function and Ras/MAPK signaling. Where specific data on CFC4 are lacking, insights are drawn from broader RASopathy research to suggest mechanistic parallels and potential therapeutic implications. Conclusions By gathering and integrating the current knowledge on MEK2 biology, this advances our understanding of MEK2-driven pathogenesis and supports the development of more effective therapeutic strategies for individuals affected by CFC4.