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Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy

Official URL:https://doi.org/10.1038/ng815
PubMed:View item in PubMed
Creators Name:Gerull, B. and Gramlich, M. and Atherton, J. and McNabb, M. and Trombitas, K. and Sasse-Klaassen, S. and Seidman, J.G. and Seidman, C. and Granzier, H. and Labeit, S. and Frenneaux, M. and Thierfelder, L.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Volume:30
Number:2
Page Range:201-204
Date:February 2002
Keywords:Base Sequence, Dilated Cardiomyopathy, DNA, DNA Mutational Analysis, Molecular Models, Molecular Sequence Data, Muscle Proteins, Mutation, Myocardium, Pedigree, Protein Folding, Protein Kinases
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.
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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