When signaling goes astray: understanding MAP2K1 mutations in neurodevelopmental disorders

The RAS/MAPK signalling pathway is one of the most extensively studied pathways, mainly due to its fundamental role in the regulation of cell cycle, proliferation, or senescence.Mutations in RAS/MAPK are primary drivers of cancer [1].They also contribute to developmental syndromes known as RASopathies.These syndromes are associated with body malformations of different severity and with impaired cognitive function.Individuals with these syndromes often experience intellectual disability (ID) and autism spectrum disorder (ASD) [2,3].In this study, we investigate de novo recurrent singlepoint missense mutations in MAP2K1 gene (encoding MEK1 protein), found in individuals with ID and ASD.They are currently classified as variants of unknown significance (VUS) [4].It is crucial to investigate whether and how they impact the protein function, as some variants in RASopathies are known to increase or decreas the kinase activity.