De novo variants of the MAPK1 gene have been identified as underlying a novel neurodevelopmental disorder within the clinical spectrum of rasopathies. This family of genetic disorders includes for example Noonan syndrome and other very rare syndromes. MAPK1 codes for ERK2, a MAP kinase. Mitogen-activated kinases, or MAP kinases, are protein kinases acting in several multi-step phosphorylation cascades that mediate nearly all cellular processes. One of these cascades is the RAS-MAPK signaling pathway, which plays an important role in cell growth and differentiation. The term rasopathies refers to a group of rare disorders in which genetic defects result in hyperactivation of RAS-MAPK signaling.

In their study published in The American Journal of Human Genetics, the researchers identified de novo missense variants of MAPK1 in seven patients who presented with a neurodevelopmental disorder that in some cases overlapped with Noonan syndrome. Functional experiments in cell lines and an animal model demonstrated that the identified variants led to increased phosphorylation of the kinase and enhanced MAPK signaling (as is also described for other rasopathies). The researchers further discovered that the variants impact on MAPK1 function in a stimulus-dependent manner by two mechanisms with counteracting effects.