Genetic variation in titin in arrhythmogenic right ventricular cardiomyopathy-overlap syndromes

Matthew Taylor, Sharon Graw, Gianfranco Sinagra, Carl Barnes, Dobromir Slavov, Francesca Brun, Bruno Pinamonti, Ernesto E. Salcedo, William Sauer, Stylianos Pyxaras, Brian Anderson, Bernd Simon, Julius Bogomolovas, Siegfried Labeit, Henk Granzier, Luisa Mestroni

Research output: Contribution to journalArticlepeer-review

211 Scopus citations


Background-: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks. Methods and results-: All 312 titin exons known to be expressed in human cardiac titin and the complete 3′ untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%). Conclusions-: Our data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.

Original languageEnglish (US)
Pages (from-to)876-885
Number of pages10
Issue number8
StatePublished - Aug 23 2011


  • arrhythmia
  • arrhythmogenic right ventricular dysplasia
  • cardiomyopathy
  • death, sudden
  • genetics

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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