The p.Ala2430Val mutation in filamin C causes a "hypertrophic myofibrillar cardiomyopathy"

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Muscle Pathophysiology

Background:

• Hypertrophic cardiomyopathy (HCM) is a primary genetic heart muscle disease often linked to sarcomeric protein mutations.
• Genetic defects remain unidentified in a significant proportion of HCM patients, hindering understanding of disease mechanisms.
• Filamin C (FLNC) gene mutations are increasingly recognized as a cause of HCM, but detailed myocardial pathology is often lacking.

Observation:

• Whole exome sequencing identified a novel FLNC mutation (c.7289C>T; p.Ala2430Val) in a patient with early-onset HCM.
• Histopathological analysis of patient myocardial tissue revealed myofibrillar disarray, Z-disc protein aggregates (BAG3, desmin, HSPB5, filamin C), and altered intercalated discs.
• Immunofluorescence and electron microscopy demonstrated Xin-positive sarcomeric lesions and reduced connexin43 expression in cardiomyocytes.

Findings:

• The FLNC p.Ala2430Val mutation is associated with a distinct pattern of myofibrillar myopathy in the heart.
• Cardiac pathology includes significant myofibril disorganization and accumulation of specific protein aggregates.
• Altered autophagy pathways, evidenced by increased LC3-II and WIPI1, suggest a role in disease progression.

Implications:

• This study provides direct molecular and ultrastructural evidence linking FLNC mutations to HCM pathology.
• Understanding the specific cellular defects caused by FLNC mutations can inform diagnostic strategies and therapeutic development for HCM.
• The findings highlight the importance of investigating Z-disc and intercalated disc abnormalities in sarcomeric cardiomyopathies.