RAF1 mutations in childhood-onset dilated cardiomyopathy

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Dilated cardiomyopathy (DCM) is a heterogeneous heart condition often linked to sarcomeric gene mutations.
• The etiology of many DCM cases remains unknown, and targeted therapies are lacking.

Purpose of the Study:

• To investigate the role of RAF1 mutations in dilated cardiomyopathy.
• To identify novel genetic causes and potential therapeutic targets for DCM.

Main Methods:

• Resequencing of 513 DCM cases and 1,150 controls across diverse ancestries.
• Biochemical analysis of RAF1 mutant kinase activity and downstream signaling (ERK, AKT).
• Zebrafish embryo studies to model DCM phenotype and test therapeutic interventions.

Main Results:

• Rare, functional RAF1 mutations identified in South Indian, North Indian, and Japanese cohorts.
• RAF1 mutations were present in approximately 9% of childhood-onset DCM cases in these cohorts.
• Mutant RAF1 caused AKT hyperactivation, leading to a heart failure phenotype in zebrafish, which was reversed by rapamycin.

Conclusions:

• RAF1 mutations represent a significant cause of childhood-onset DCM in specific populations.
• RAF1-associated DCM involves AKT hyperactivation and presents a potential therapeutic target.
• This study expands the known clinical spectrum of RAF1-related disorders.