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RASopathies and cardiac manifestations
Nazia Hilal1,2,3, Zi Chen2,4, Ming Hui Chen2,5
1Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, United States.
Frontiers in Cardiovascular Medicine
|August 2, 2023
Summary
RAS proteins act as on/off switches, but mutations cause RASopathies, leading to developmental disorders and heart conditions. Understanding RAS regulation is key to diagnosing and treating these complex genetic syndromes.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- RAS proteins function as binary switches, cycling between ON/OFF states for cellular signaling.
- Mutations in RAS or its regulators lead to constitutive activation, causing diseases like cancer and RASopathies.
- RAS/MAPK pathway genes are crucial for cell cycle, proliferation, differentiation, growth, and metabolism.
Purpose of the Study:
- To elucidate the regulatory mechanisms of RAS proteins.
- To clarify the link between RASopathies and cardiovascular conditions like cardiomyopathy and congenital heart disease.
- To address diagnostic challenges posed by genetic heterogeneity and allelism in RAS/MAPK syndromes.
Main Methods:
- Review of existing literature on RAS protein regulation and RASopathies.
- Analysis of genetic data related to RAS/MAPK pathway mutations.
- Examination of clinical manifestations, including cardiovascular defects, in RASopathy patients.
Main Results:
- RASopathies, caused by germline mutations in the RAS/MAPK pathway, affect 1 in 1,000-2,500 children.
- Syndromes include Noonan syndrome, cardio-facio-cutaneous syndrome, Costello syndrome, and LEOPARD syndrome.
- RASopathies are frequently associated with cardiomyopathy and congenital heart disease, though evidence is still developing.
Conclusions:
- Despite progress, the precise regulatory mechanisms of RAS proteins remain incompletely understood.
- Genetic complexity and allelism complicate the diagnosis of RAS/MAPK-related disorders.
- Unidentified causal genes persist for a significant number of RASopathy patients, highlighting the need for further research.
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