Abstract
Congestive heart failure (CHF) can result from various disease states with inadequate cardiac output. CHF due to dilated cardiomyopathy (DCM) is a familial disease in 20-30% of cases and is associated with mutations in genes encoding cytoskeletal, contractile or inner-nuclear membrane proteins. We show that mutations in the gene encoding giant-muscle filament titin (TTN) cause autosomal dominant DCM linked to chromosome 2q31 (CMD1G; MIM 604145). Titin molecules extend from sarcomeric Z-discs to M-lines, provide an extensible scaffold for the contractile machinery and are crucial for myofibrillar elasticity and integrity. In a large DCM kindred, a segregating 2-bp insertion mutation in TTN exon 326 causes a frameshift, truncating A-band titin. The truncated protein of approximately 2 mD is expressed in skeletal muscle, but western blot studies with epitope-specific anti-titin antibodies suggest that the mutant protein is truncated to a 1.14-mD subfragment by site-specific cleavage. In another large family with DCM linked to CMD1G, a TTN missense mutation (Trp930Arg) is predicted to disrupt a highly conserved hydrophobic core sequence of an immunoglobulin fold located in the Z-disc-I-band transition zone. The identification of TTN mutations in individuals with CMD1G should provide further insights into the pathogenesis of familial forms of CHF and myofibrillar titin turnover.
Original language | English |
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Pages (from-to) | 201-4 |
Number of pages | 4 |
Journal | Nature Genetics |
Volume | 30 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 2002 |
Keywords
- Base Sequence
- Cardiomyopathy, Dilated
- Connectin
- DNA
- DNA Mutational Analysis
- Female
- Humans
- Male
- Models, Molecular
- Molecular Sequence Data
- Muscle Proteins
- Mutation
- Myocardium
- Pedigree
- Protein Folding
- Protein Kinases