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

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Item Type:	Article
Title:	Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy
Creators Name:	Gerull, B., Gramlich, M., Atherton, J., McNabb, M., Trombitas, K., Sasse-Klaassen, S., Seidman, J.G., Seidman, C., Granzier, H., Labeit, S., Frenneaux, M. and Thierfelder, L.
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.
Keywords:	Base Sequence, Dilated Cardiomyopathy, DNA, DNA Mutational Analysis, Molecular Models, Molecular Sequence Data, Muscle Proteins, Mutation, Myocardium, Pedigree, Protein Folding, Protein Kinases
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	30
Number:	2
Page Range:	201-204
Date:	February 2002
Official Publication:	https://doi.org/10.1038/ng815
PubMed:	View item in PubMed

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