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

Brenda Gerull, John Atherton, Anke Geupel, Sabine Sasse-Klaassen, Arnd Heuser, Michael Frenneaux, Mark McNabb, Hendrikus "Henk" Granzier, Siegfried Labeit, Ludwig Thierfelder

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)478-483
Number of pages6
JournalJournal of Molecular Medicine
Volume84
Issue number6
DOIs
StatePublished - May 2006
Externally publishedYes

Fingerprint

Connectin
Frameshift Mutation
Dilated Cardiomyopathy
Muscles
Mutation
Sequence Deletion
Penetrance
Nonsense Codon
Pedigree
Post Translational Protein Processing
Proteolysis
Dilatation
Heart Diseases
Protein Isoforms
Skeletal Muscle
Phenotype
Biopsy
Amino Acids
Messenger RNA

Keywords

  • Dilated cardiomyopathy
  • Frameshift mutation
  • Titin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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, Hendrikus "Henk"; Labeit, Siegfried; Thierfelder, Ludwig.

In: Journal of Molecular Medicine, Vol. 84, No. 6, 05.2006, p. 478-483.

Research output: Contribution to journalArticle

Gerull, B, Atherton, J, Geupel, A, Sasse-Klaassen, S, Heuser, A, Frenneaux, M, McNabb, M, Granzier, HH, Labeit, S & Thierfelder, L 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, vol. 84, no. 6, pp. 478-483. https://doi.org/10.1007/s00109-006-0060-6
Gerull, Brenda ; Atherton, John ; Geupel, Anke ; Sasse-Klaassen, Sabine ; Heuser, Arnd ; Frenneaux, Michael ; McNabb, Mark ; Granzier, Hendrikus "Henk" ; Labeit, Siegfried ; Thierfelder, Ludwig. / Identification of a novel frameshift mutation in the giant muscle filament titin in a large Australian family with dilated cardiomyopathy. In: Journal of Molecular Medicine. 2006 ; Vol. 84, No. 6. pp. 478-483.
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