NSEURONET: European Network on Noonan syndrome and related disorders

RASopathies constitute the most common family of non-chromosomal disorders affecting development. This group of rare diseases includes an increasing number of conditions characterized by reduced growth, heart defects, cognitive deficits, dysmorphisms and variable predisposition to malignancies. RASopathies share upregulated RAS-MAPK and/or PI3K-AKT-mTOR signaling as pathogenetic mechanism. Past work of the NSEuroNet partners has significantly contributed to our understanding of the molecular causes underlying these diseases and to their clinical characterization. However, we are still far from a full understanding of the impact of mutations on protein function, intracellular signaling, and cell physiology. Considering the availability of molecules targeting the signaling pathways altered in RASopathies, a deeper knowledge of the functional impact of individual mutations is required for designing effective therapies. Finally, a significant number of patients remains molecularly unexplained. The planned work, which is the natural follow-up of a previously funded E-Rare project, is directed to resolve the functional consequences of a large panel of uncharacterized mutations, generate in vitro and in vivo gene/mutation-specific models, characterize novel circuits modulating RAS signaling, explore the pathophysiology of key complications of these diseases, and identify novel disease genes. Work will also be directed to populate a dedicated database that will be used for clinically oriented studies to help clinicians towards a timely diagnosis and a more effective patient care.