Genetic Variation in Titin in Arrhythmogenic Right Ventricular Cardiomyopathy–Overlap Syndromes

Abstract

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 one large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain), located in titin’s spring region. Native gel electrophoresis, NMR, intrinsic fluorescence, and proteolysis assays of wildtype and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity towards degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by history of sudden death (5/7 families), progressive myocardial dysfunction causing death or heart transplant (8/14 cases), frequent conduction disease (11/14), 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.

Gigantic Business

“…98 The 8 arrhythmogenic right ventricular cardiomyopathyassociated mutations identified to date are distributed all over the TTN sequence. 99 Some TTN mutations disrupt the interaction of the protein with binding partners (Online Table I) and may compromise the functions of titin in myofibril assembly or mechanical signaling. Specific mutations in I-band Ig domains could weaken the structural integrity of these domains and thus be disease causing, as suggested for a proximal titin-Ig-domain mutated in arrhythmogenic right ventricular cardiomyopathy.…”

Biophysics of Titin in Cardiac Health and Disease

“…Genetic analysis of 38 well-characterized AC families identified a C39453T nucleotide transition in the 37 th exon of titin that showed complete segregation with the AC phenotype in six affected patients [37]. In addition, two fifth-degree relatives with AC shared this mutation, which strongly suggests that the mutation is linked with the disease phenotype.…”

“…Mutations in titin have been associated with dilated cardiomyopathy [36], but recently a mutation in titin was linked with arrhythmogenic cardiomyopathy (AC) for the first time [37]. AC has been termed a "disease of the desmosome" because numerous desmosomal mutations have been identified that cause the disease phenotype [31].…”

Recent Developments in the Genetics of Cardiomyopathies

“…Although the functional role of titin in the cardiomyocyte are known, the effects of TTN truncating mutations on the exact pathophysiology of DCM have yet to be defined. To complicate matters further, titin mutations have also recently been associated with ARVC [25]. Much work therefore remains to analyse and validate these exciting genetic data before they can be applied clinically.…”