Ras/MAPK Pathway Dysregulation in Genetic Syndromes

The Ras/mitogen-activated protein kinase (MAPK) pathway is a central signalling cascade that transmits extracellular growth and differentiation cues to nuclear effectors. Germline mutations in components or regulators of this pathway give rise to a group of developmental disorders collectively known as RASopathies. These include Noonan, LEOPARD, cardiofaciocutaneous and Costello syndromes, which share features such as congenital cardiac defects, distinctive craniofacial morphology, cutaneous anomalies and variable neurocognitive impairment. Pathogenic variants often result in constitutive activation or impaired inactivation of RAS GTPases or downstream kinases, leading to aberrant cell proliferation, differentiation and morphogenesis during embryogenesis. Advances in genomic diagnostics and model organisms have clarified genotype–phenotype correlations and revealed tissue-specific sensitivities to hyperactive MAPK signalling. This knowledge underpins a growing interest in targeted therapies—such as MEK and mTOR inhibitors—which hold promise for ameliorating cardiac hypertrophy, neurodevelopmental delay and other cardinal manifestations of RASopathies. Ongoing research strives to refine treatment windows, minimise off-target effects and extend interventions beyond oncological contexts into rare inherited disorders.

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Ras/MAPK Pathway Dysregulation in Genetic Syndromes publication trend

The graph below shows the total number of articles in ras/mapk pathway dysregulation in genetic syndromes across all publications each year (not limited to Nature Index journals).

Technical terms

RASopathy: Developmental syndrome caused by germline mutations in RAS/MAPK pathway genes, characterised by overlapping cardiac, craniofacial and neurocognitive anomalies.

GTPase: Enzyme that binds and hydrolyses guanosine triphosphate (GTP), acting as a molecular switch in signal transduction.

MAPK cascade: Sequential activation of kinases (RAF, MEK, ERK) downstream of RAS that regulate cell proliferation, differentiation and survival.

SHP2 (PTPN11): Cytoplasmic protein tyrosine phosphatase encoded by PTPN11; its regulatory role in RAS/MAPK signalling underlies syndromes such as Noonan and LEOPARD.

MEK inhibitor: Small molecule that selectively blocks MEK kinase activity, thereby attenuating downstream ERK phosphorylation and MAPK pathway output.

References

1. Combined HRAS and NRAS ablation induces a RASopathy phenotype in mice. Cell Communication and Signaling (2024).
2. Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities. Translational Psychiatry (2023).
3. The RASopathies: from pathogenetics to therapeutics. Disease Models & Mechanisms (2022).