Abstract 17211: Titin Mutations Cause Arrhythmogenic Right Ventricular Cardiomyopathy
Purpose: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. ARVC is familial in up to 50% of cases and current disease models implicate desmosomal dysfunction as the fundamental pathogenic defect. We evaluated the cardiomyopathy gene titin (TTN) as an ARVC candidate as it is close to the ARVD4 locus and the titin protein connects to the transitional junction at intercalated disks.
Methods: Patients from 38 ARVC families underwent TTN DNA resequencing provided by the University of Washington, Department of Genome Sciences. Exons and peri-exonic regions of titin isoform N2A (NM_133378) along with additional exons unique to the principal cardiac isoform N2B (NM_003319) were amplified from genomic DNA using PCR. This covered 312 exons (311 expressed as titin protein) and the complete 3′ untranslated region. Four of the ARVC families were sufficiently large to test for cosegregation of TTN mutations with the ARVC phenotype and are reported here.
Results: Four, unique TTN variants were detected in the four families (Thr2896Ile, Ile16949Thr, Pro17706Leu, Ala19309Ser). The Thr2896Ile variant showed compelling genetic evidence that is pathogenic: present in 9 confirmed/obligate ARVC subjects including 2 fifth-degree relatives, absent in over 350 cardiomyopathy and 176 control chromosomes, and was scored ‘intolerant’ by SIFT and PolyPhen predictive algorithms. Ile16949Thr and Ala19309 were absent in controls and segregated with ‘affected’ status in smaller ARVC pedigrees and are suggestive for being pathogenic. Pro17706Leu, although ‘intolerant’ and unique, is likely a rare benign polymorphism since it was inherited from the unaffected parent.
Conclusions: Our data show that titin mutations may cause ARVC; disruption of normal spring-recoil properties of the titin protein may account for the phenotype manifestations in the thinner-walled stress-susceptible right ventricle.
- © 2010 by American Heart Association, Inc.