title: Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy.
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.
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, D-13092 Berlin-Buch, Germany.
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
authors.forename: Michael
authors.initials: M
authors.lastname: Gramlich
authors.forename: John
authors.initials: J
authors.lastname: Atherton
authors.forename: Mark
authors.initials: M
authors.lastname: McNabb
authors.forename: Karoly
authors.initials: K
authors.lastname: Trombitás
authors.forename: Sabine
authors.initials: S
authors.lastname: Sasse-Klaassen
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Christine
authors.initials: C
authors.lastname: Seidman
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
authors.forename: Michael
authors.initials: M
authors.lastname: Frenneaux
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
mesh_terms: D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D064211:Connectin; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D010375:Pedigree; D017510:Protein Folding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*
chemical_list: D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D004247:DNA; D011494:Protein Kinases