VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Medicine

Background:

• Dilated cardiomyopathy (DCM) is a primary cause of heart failure and sudden cardiac death, characterized by ventricular dilation and dysfunction.
• While over 100 genes are linked to DCM, genetic defects remain unidentified in many cases due to significant genetic heterogeneity.
• Identifying novel genetic determinants is crucial for understanding DCM's molecular pathogenesis and improving patient management.

Purpose of the Study:

• To identify novel genetic factors contributing to the development of dilated cardiomyopathy (DCM).
• To investigate the role of the VEZF1 gene in the pathogenesis of familial DCM.

Main Methods:

• Whole-exome sequencing and bioinformatics analysis were performed on a family with DCM.
• A novel heterozygous nonsense mutation (c.490A>T; p.(Lys164*)) in the VEZF1 gene was identified and validated by Sanger sequencing.
• Dual-luciferase reporter assays were used to assess the functional impact of the mutant VEZF1 on downstream gene promoters (MYH7, ET1).

Main Results:

• A novel, pathogenic heterozygous nonsense mutation in the VEZF1 gene was identified and segregated with autosomal dominant DCM in the studied family.
• The identified VEZF1 mutation was absent in control cohorts of DCM patients and healthy individuals, and not found in public databases.
• Functional assays demonstrated that the mutant VEZF1 protein lost its ability to transactivate the MYH7 and ET1 gene promoters, both implicated in DCM.

Conclusions:

• VEZF1 is identified as a novel causative gene for dilated cardiomyopathy.
• The findings elucidate a new molecular mechanism in DCM pathogenesis involving VEZF1 dysfunction.
• This discovery may pave the way for personalized precision medicine approaches in managing DCM patients.