Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy

Gerull, Brenda, Atherton, John, Geupel, Anke, Sasse-Klaassen, Sabine, Heuser, Arnd, Frenneaux, Michael, McNabb, Mark, Granzier, Henk, Labeit, Siegfried and Thierfelder, Ludwig (2006) Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. Journal of Molecular Medicine, 84 (6). pp. 478-83. ISSN 0946-2716

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Dilated cardiomyopathy (DCM) is an etiologically heterogeneous cardiac disease characterized by left ventricular dilation and systolic dysfunction. Approximately 25-30% of DCM patients show a family history of mainly autosomal dominant inheritance. We and others have previously demonstrated that mutations in the giant muscle filament titin (TTN) can cause DCM. However, the prevalence of titin mutations in familial DCM is unknown. In this paper, we report a novel heterozygous 1-bp deletion mutation (c.62890delG) in TTN that cosegregates with DCM in a large Australian pedigree (A3). The TTN deletion mutation c.62890delG causes a frameshift, thereby generating a truncated A-band titin due to a premature stop codon (p.E20963KfsX10) and the addition of ten novel amino acid residues. The clinical phenotype of DCM in kindred A3 demonstrates incomplete penetrance and variable expressivity. Finally, protein analysis of a skeletal muscle biopsy sample from an affected member did not reveal the predicted truncated titin isoform although the aberrant mRNA was present, suggesting posttranslational modification and degradation of the truncated protein. The identification of a novel disease-causing mutation in the giant titin gene in a third large family with DCM indicates that mutations in titin may account for a significant portion of the genetic etiology in familial DCM.

Item Type: Article
Uncontrolled Keywords: adult,aged,aged, 80 and over,australia,cardiomyopathy, dilated,chromosomes, human, pair 2,connectin,female,frameshift mutation,genetic linkage,humans,male,middle aged,muscle proteins,muscle, skeletal,pedigree,protein denaturation,protein kinases,protein processing, post-translational
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Depositing User: Pure Connector
Date Deposited: 23 Mar 2015 13:42
Last Modified: 23 Apr 2023 01:03
DOI: 10.1007/s00109-006-0060-6

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