Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
- 14 January 2002
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 30 (2), 201-204
- https://doi.org/10.1038/ng815
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 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.Keywords
This publication has 19 references indexed in Scilit:
- The Complete Gene Sequence of Titin, Expression of an Unusual ≈700-kDa Titin Isoform, and Its Interaction With Obscurin Identify a Novel Z-Line to I-Band Linking SystemCirculation Research, 2001
- Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domainJournal of Molecular Biology, 2001
- The Genetic Basis for Cardiomyopathy: from Mutation Identification to Mechanistic ParadigmsCell, 2001
- Series of Exon-Skipping Events in the Elastic Spring Region of Titin as the Structural Basis for Myofibrillar Elastic DiversityCirculation Research, 2000
- Differential Expression of Cardiac Titin Isoforms and Modulation of Cellular StiffnessCirculation Research, 2000
- Titin: a molecular control freakTrends in Cell Biology, 1999
- Familial Dilated Cardiomyopathy Locus Maps to Chromosome 2q31Circulation, 1999
- Muscle assembly: a titanic achievement?Current Opinion in Cell Biology, 1999
- Nonuniform elasticity of titin in cardiac myocytes: a study using immunoelectron microscopy and cellular mechanicsBiophysical Journal, 1996
- Titins: Giant Proteins in Charge of Muscle Ultrastructure and ElasticityScience, 1995