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

Gerull, Brenda, Gramlich, Michael, Atherton, John, McNabb, Mark, Trombitás, Karoly, Sasse-Klaassen, Sabine, Seidman, J G, Seidman, Christine, Granzier, Henk, Labeit, Siegfried, Frenneaux, Michael and Thierfelder, Ludwig (2002) Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nature Genetics, 30 (2). pp. 201-4. ISSN 1061-4036

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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.

Item Type: Article
Uncontrolled 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
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 09 Mar 2015 07:30
Last Modified: 21 Mar 2019 11:16
URI: https://ueaeprints.uea.ac.uk/id/eprint/52442
DOI: 10.1038/ng815

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