Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor...

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology

Background:

• Dilated cardiomyopathy (DCM) involves left ventricular dilation and systolic dysfunction, often linked to sarcomere or cytoskeleton gene mutations.
• Genetic mutations account for less than half of familial DCM cases, indicating the need to identify additional disease genes.
• FHOD3, a sarcomeric protein crucial for myofibrillogenesis, is implicated in sarcomere organization.

Purpose of the Study:

• To investigate FHOD3 as a potential novel disease gene for DCM.
• To explore the role of FHOD3 mutations in the pathogenesis of familial DCM.

Main Methods:

• Genetic analysis of 48 Japanese familial DCM patients for FHOD3 mutations.
• Functional studies using neonatal rat cardiomyocytes to assess the impact of the identified FHOD3 variant on cellular processes.
• Prediction of the variant's effect on protein structure and function.

Main Results:

• A missense variant, FHOD3 Tyr1249Asn, was identified in an adult-onset DCM patient.
• The Tyr1249Asn variant was predicted to alter protein 3D structure and impair protein function.
• Functional assays showed the mutation significantly reduced the induction of serum response factor activation via actin dynamics, without affecting cellular localization.

Conclusions:

• The identified FHOD3 Tyr1249Asn variant is associated with DCM.
• This FHOD3 variant may contribute to DCM by disrupting actin filament assembly.
• FHOD3 is a potential novel genetic factor in the etiology of dilated cardiomyopathy.