DeCure for Rasopathy

The RASopathies: from pathogenetics to therapeutics

AbstractThe RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.

Defining RASopathy

AbstractThe term RASopathy was originally created to describe a phenotypically similar group of medical genetic syndromes caused by germline pathogenic variants in components of the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway. In defining a RASopathy syndrome, one needs to consider the complex nature of the RAS/MAPK pathway, the numerous genes and regulatory components involved, its crosstalk with other signaling pathways and the phenotypic spectrum among these syndromes. Three main guiding principles to the definition should be considered. First, a RASopathy is a clinical syndrome with overlapping phenotypic features caused by germline pathogenic variants associated with the RAS/MAPK pathway. Second, a RASopathy is caused by multiple pathogenetic mechanisms, all of which lead to a similar outcome of RAS/MAPK pathway activation/dysregulation. Finally, because a RASopathy has dysfunctional germline RAS/MAPK pathway activation/dysregulation, it may, therefore, be amenable to treatment with pathway modulators.

The seventh international <scp>RASopathies</scp> symposium: Pathways to a cure—expanding knowledge, enhancing research, and therapeutic discovery

AbstractRASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.

Cover Image, Volume 190, Number 1, March 2022

AbstractCover image: RASopathy genes and the role of their encoded proteins in the RAS‐MAPK signaling cascades. Cartoon lists the genes implicated in RASopathies and their year of discovery. Genes requiring further clinical delineation and/or functional validation in the context of the RASopathies are shown in red. Milestones linked to these discoveries are also reported. D and R indicate dominant and recessive, respectively. Below the figure of gene discovery timeline, the RAS‐MAPK signaling cascade showing the signal flow through the pathway (black arrows), together with the proteins positively (blue) and negatively (red) controlling the cascade, is presented. P and Ub indicate phosphorylation and ubiquitination, respectively. For further explanations see Figure 1 legend from paper by Tartaglia et al. (present issue). Image also shows pictures of some individuals affected by RASopathies. image

AbstractCover image: RASopathy genes and the role of their encoded proteins in the RAS-MAPK signaling cascades. Cartoon lists the genes implicated in RASopathies and their year of discovery. Genes requiring further clinical delineation and/or functional validation in the context of the RASopathies are shown in red. Milestones linked to these discoveries are also reported. D and R indicate dominant and recessive, respectively. Below the figure of gene discovery timeline, the RAS-MAPK signaling cascade showing the signal flow through the pathway (black arrows), together with the proteins positively (blue) and negatively (red) controlling the cascade, is presented. P and Ub indicate phosphorylation and ubiquitination, respectively. For further explanations see Figure 1 legend from paper by Tartaglia et al. (present issue). Image also shows pictures of some individuals affected by RASopathies.