Nature Genetics
30, 201 - 204 (2002)
Published online: 14 January 2002; | doi:10.1038/ng815
Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathyBrenda Gerull1, 2, 9, Michael Gramlich1, 9, John Atherton3, Mark McNabb4, Karoly Trombitás4, Sabine Sasse-Klaassen1, J.G. Seidman5, Christine Seidman6, Henk Granzier4, Siegfried Labeit7, Michael Frenneaux8
& Ludwig Thierfelder1, 21
Max-Delbrueck Center for Molecular Medicine, D-13092 Berlin-Buch, Germany. 2
HELIOS Kliniken GmbH, Franz-Volhard Klinik, Charité, Humboldt-University, Berlin, Germany. 3
Department of Cardiology, Royal Brisbane Hospital, Brisbane, Australia. 4
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 99164-6520, USA. 5
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston Massachusetts 02115, USA. 6
Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA, 7
Anesthesiology and Intensive Operative Medicine, University Hospital Mannheim, D-68135 Mannheim, Germany. 8
Department of Cardiology, University of Wales College of Medicine, Cardiff, UK. 9
These authors contributed equally to this work.
Correspondence should be addressed to Ludwig Thierfelder lthier@mdc-berlin.deCongestive 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 proteins1. 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 integrity2. 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.
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