Abstract 2816: Cardiac Troponin T Mutation Causes Familial Restrictive Cardiomyopathy with Variable Remodeling
Introduction: The three types of cardiomyopathy - dilated (DCM), hypertrophic (HCM), and restrictive (RCM) - may be triggered by similar or identical molecular defects. TNNI3, also implicated in HCM and DCM, is the only known gene for primary RCM.
Methods: A family with autosomal dominant RCM was phenotypically characterized. Polymorphic DNA markers for 9 sarcomeric genes for DCM and/or HCM were tested for segregation with disease. Once implicated as a candidate gene, cardiac troponin T (TNNT2) was sequenced.
Results: Genetic linkage to 8 of 9 candidate genes was excluded, but a marker for TNNT2 co-segregated with the disease phenotype. Sequencing of TNNT2 identified a heterozygous missense mutation resulting in an I79N substitution. The mutation was inherited by all 9 affected family members but by none of the 6 unaffected relatives. Age at disease onset was 40 to 68 yrs. All mutation-carriers exhibited diagnostic features of RCM: massive biatrial enlargement with elevated filling pressures and restrictive filling patterns by Doppler. Cardiac hypertrophy and ventricular dilation with systolic dysfunction, morphologic features of HCM and DCM, were observed in a subset. Hypertrophy, present in 4, was localized to the mid and apical septum and was without associated systolic anterior motion of the mitral valve or outflow tract obstruction. Progression to ventricular dilation and systolic dysfunction occurred in 4 by the seventh decade of life. Endomyocardial biopsies revealed nonspecific fibrosis, myocyte hypertrophy, and lack of myofibrillar disarray. Arrhythmias including atrial flutter/fibrillation, sinus node dysfunction, and complete heart block were observed in 8 of 9 mutation-carriers. There were no sustained ventricular arrhythmias. Three mutation-carriers died between 64 and 74 years; two deaths were cardiac related.
Conclusion: This is the first description of a TNNT2 mutation causing familial RCM. The identical I79N substitution, previously reported in HCM, has been functionally characterized in transgenic mice, which exhibit altered Ca2+-myofilament kinetics and recapitulate the RCM phenotype observed in our family.