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

Item Type:	Article
Title:	Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy
Creators Name:	Gerull, B. and Atherton, J. and Geupel, A. and Sasse-Klaassen, S. and Heuser, A. and Frenneaux, M. and McNabb, M. and Granzier, H. and Labeit, S. and Thierfelder, L.
Abstract:	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.
Keywords:	Dilated Cardiomyopathy, Titin, Frameshift Mutation
Source:	Journal of Molecular Medicine
ISSN:	0946-2716
Publisher:	Springer
Volume:	84
Number:	6
Page Range:	478-483
Date:	June 2006
Official Publication:	https://doi.org/10.1007/s00109-006-0060-6
PubMed:	View item in PubMed

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