Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Heart Failure Pathophysiology

Background:

• Idiopathic dilated cardiomyopathy (DCM) is a myocardial disorder with unknown molecular basis, leading to reduced contractile function.
• Familial DCM cases linked to cardiac cytoskeletal protein mutations suggest impaired contractile-force transmission.
• Investigating genetic causes is crucial for understanding this heart failure etiology.

Purpose of the Study:

• To elucidate genetic causes of familial dilated cardiomyopathy (DCM).
• To identify mutations in sarcomere protein genes associated with DCM.
• To understand the link between sarcomere protein defects and heart remodeling.

Main Methods:

• Clinical evaluations of 21 kindreds with familial DCM.
• Genome-wide linkage studies to identify genetic loci.
• Screening of genes encoding beta-myosin heavy chain, troponin T, troponin I, and alpha-tropomyosin for mutations.

Main Results:

• Identified a genetic locus for DCM mutations at chromosome 14q11.2-13, encoding cardiac beta-myosin heavy chain.
• Discovered disease-causing dominant mutations in sarcomere protein genes in four kindreds.
• Specific mutations (Ser532Pro, Phe764Leu in beta-myosin heavy chain; deltaLys210 in troponin T) caused early-onset ventricular dilatation, dysfunction, and heart failure without prior hypertrophy.

Conclusions:

• Sarcomere protein gene mutations account for ~10% of familial DCM, especially with early-onset ventricular dilatation.
• Distinct sarcomere protein mutations can cause either DCM or hypertrophic cardiomyopathy.
• Mutant sarcomere proteins trigger different molecular events leading to distinct heart remodeling pathways.