The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

Noonan syndrome is a pleomorphic genetic disorder, in which a high percentage of affected individuals have cardiovascular involvement, most prevalently various forms of congenital heart disease (i.e., pulmonary valve stenosis, septal defects, left‐sided lesions, and complex forms with multiple anomalies). Care includes attentiveness to several comorbidities, some directly impacting cardiac management (bleeding diatheses and lymphatic anomalies). More than 50% of patients with Noonan syndrome harbor PTPN11 pathogenic variation, which results in hyperactivation of RAS/mitogen‐activated protein kinase signaling. Several other disease genes with similar biological effects have been uncovered for NS and phenotypically related disorders, collectively called the RASopathies. Molecular diagnosis with gene resequencing panels is now widely available, but phenotype variability and in some cases, subtlety, continues to make identification of Noonan syndrome difficult. Until genetic testing becomes universal for patients with congenital heart disease, alertness to Noonan syndrome's broad clinical presentations remains crucial. Genotype–phenotype associations for Noonan syndrome enable better prognostication for affected patients when a molecular diagnosis is established. We still lack Noonan syndrome‐specific treatment; however, newly developed anticancer RAS pathway inhibitors could fill that gap if safety and efficacy can be established for indications such as pulmonary valve stenosis.

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“…Citations for Table 1: Tidyman and Rauen (); Aoki et al (); Yamamoto et al (); Tajan, Paccoud, Branka, Edouard, and Yart (); Yu et al ().…”

Section: Noonan Syndrome and The Rasopathiesmentioning

confidence: 99%

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Linglart

Gelb

2020

American J of Med Genetics Pt C

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“…Additionally, the risk of discovering germ line variants that are unrelated or only peripherally related to hematologic malignancies is also problematic. For instance, variants in EZH2 are associated with Weaver syndrome, and mutations in a range of genes are associated with RASopathies such as Noonan syndrome . As panel sizes increase, so does the risk of detecting incidental findings unrelated to the clinical questions at hand.…”

Section: How Should Patients Be Screened?mentioning

confidence: 99%

Genomic testing in myeloid malignancy

Docking

Karsan

2019

Int J Lab Hematology

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Clinical genetic testing in the myeloid malignancies is undergoing a rapid transition from the era of cytogenetics and single‐gene testing to an era dominated by next‐generation sequencing (NGS). This transition promises to better reveal the genetic alterations underlying disease, but there are distinct risks and benefits associated with different NGS testing platforms. NGS offers the potential benefit of being able to survey alterations across a wider set of genes, but analytic and clinical challenges associated with incidental findings, germ line variation, turnaround time, and limits of detection must be addressed. Additionally, transcriptome‐based testing may offer several distinct benefits beyond traditional DNA‐based methods. In addition to testing at disease diagnosis, research indicates potential benefits of genetic testing both prior to disease onset and at remission. In this review, we discuss the transition from the era of cytogenetics and single‐gene tests to the era of NGS panels and genome‐wide sequencing—highlighting both the potential and drawbacks of these novel technologies.

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“…Among them are RASopathies, which include the Noonan, Costello and cardio-facio-cutaneous (CFC) syndromes [103, 104], extracranial arteriovenous malformation [105], and Kabuki syndrome [106]. These last disorders can be induced by activating the mutation of MEK (CFC) or upstream components of the ERK1/2 cascade [107]. Elevated ERK1/2 activity was also implicated in the induction of neurological disorders [108], diabetes [109] and other diseases [3].…”

Section: Mapk Cascades In Diseasementioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

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The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

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The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway

Cited by 175 publications

References 261 publications

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment

Genomic testing in myeloid malignancy

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

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