Journal of Molecular Medicine

, Volume 84, Issue 6, pp 478–483

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
  • Henk Granzier
  • Siegfried Labeit
  • Ludwig Thierfelder
Original Article

DOI: 10.1007/s00109-006-0060-6

Cite this article as:
Gerull, B., Atherton, J., Geupel, A. et al. J Mol Med (2006) 84: 478. doi:10.1007/s00109-006-0060-6

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 

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Brenda Gerull
    • 1
    • 2
  • John Atherton
    • 3
  • Anke Geupel
    • 1
    • 2
  • Sabine Sasse-Klaassen
    • 1
  • Arnd Heuser
    • 1
  • Michael Frenneaux
    • 4
  • Mark McNabb
    • 5
  • Henk Granzier
    • 5
  • Siegfried Labeit
    • 6
  • Ludwig Thierfelder
    • 1
    • 2
  1. 1.Max-Delbrueck Center for Molecular MedicineBerlin-BuchGermany
  2. 2.Department of Clinical and Molecular Cardiology, Franz-Volhard Clinic, HELIOS Clinics GmbH, CharitéHumboldt UniversityBerlinGermany
  3. 3.Department of CardiologyRoyal Brisbane and Women’s Hospital, University of QueenslandBrisbaneAustralia
  4. 4.Department of Cardiovascular MedicineUniversity of BirminghamEdgbastonUK
  5. 5.VCAPPWashington State UniversityPullmanUSA
  6. 6.Anesthesiology and Intensive Operative MedicineUniversity Hospital MannheimMannheimGermany