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

Research output: Contribution to journalLetter

Authors

  • B Gerull
  • M Gramlich
  • J Atherton
  • M McNabb
  • K Trombitas
  • S Sasse-Klaassen
  • JG Seidman
  • H Granzier
  • S Labeit
  • L Theirfelder

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)201-204
Number of pages4
JournalNature Genetics
Volume30
Issue number2
Publication statusPublished - 1 Feb 2002