Mutations in ILK, encoding integrin-linked kinase, are associated with arrhythmogenic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Basis of Heart Disease

Background:

• Arrhythmogenic cardiomyopathy (ACM) is a genetic heart disorder causing arrhythmias and sudden cardiac death, often due to mutations in cardiac junctional protein genes.
• The genetic causes for approximately half of ACM cases remain unknown, necessitating the identification of novel disease genes.

Purpose of the Study:

• To identify novel genetic variants associated with arrhythmogenic cardiomyopathy.
• To investigate the functional impact of identified variants in the integrin-linked kinase (ILK) gene on cardiac function.

Main Methods:

• Exome sequencing was used to identify variants in the ILK gene in patients with ACM.
• In silico binding studies and cell-based assays (H9c2 cells) were performed to assess the impact of variants on ILK protein function and localization.
• Zebrafish models expressing human wild-type and mutant ILK were used to evaluate cardiac function and survival.

Main Results:

• Two novel, predicted damaging missense variants (p.H33N and p.H77Y) in the ILK gene were identified in unrelated families with ACM.
• The p.H33N variant was found to be de novo.
• Mutant ILK showed aberrant cytoplasmic localization in vitro, and zebrafish expressing mutant ILK (p.H77Y and previously reported p.P70L) exhibited cardiac dysfunction and mortality.

Conclusions:

• Integrin-linked kinase (ILK) is a novel cardiomyopathy disease gene.
• The identified ILK variants disrupt ILK-PINCH complex formation and lead to cardiac dysfunction.
• These findings are crucial for the diagnosis and genetic counseling of inherited cardiomyopathies.