Mutations in Cypher/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction

Area of Science:

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

Background:

• Dilated cardiomyopathy (DCM) is a heart condition with genetic links in 30-40% of cases, caused by mutations in cytoskeletal and sarcomeric genes.
• Isolated non-compaction of the left ventricular myocardium (INLVM) is also inherited, with distinct genetic causes from DCM.
• Cypher/ZASP is a recently identified gene crucial for Z-line structure in skeletal and cardiac muscle.

Purpose of the Study:

• To investigate the role of the Cypher/ZASP gene in the development of dilated cardiomyopathy (DCM).
• To assess the involvement of Cypher/ZASP in cases of DCM with or without isolated non-compaction of the left ventricular myocardium (INLVM).

Main Methods:

• Diagnosis of DCM and INLVM involved echocardiography, electrocardiography, and physical examinations.
• Muscular creatine kinase levels were measured to detect skeletal muscle involvement.
• Cypher/ZASP gene screening was performed using denaturing high-performance liquid chromatography (DHPLC) and DNA sequencing.

Main Results:

• Mutations in the Cypher/ZASP gene were identified in 6% of probands with left ventricular dysfunction (5 mutations in 6 patients).
• These mutations were found in patients diagnosed with familial or sporadic DCM or INLVM.
• In vitro experiments demonstrated that mutated Cypher/ZASP disrupts cytoskeleton organization.

Conclusions:

• Mutations in the Cypher/ZASP gene are implicated as a cause of DCM and INLVM.
• This study provides a mechanistic understanding of how Cypher/ZASP mutations lead to these cardiac conditions.