Abstract 1891: Severe Familial Left Ventricular Noncompaction Cardiomyopathy Due to a Novel Troponin T Mutation
Left ventricular noncompaction cardiomyopathy (LVNC) has recently been recognized as a distinct entity of inherited heart disease. LVNC is caused by mutations in multiple genes, including several that encode for sarcomeric proteins. Yet, it is still unclear whether the noncompaction phenotype is the primary determinant of cardiomyopathy or rather a secondary phenomenon, with intrinsic cardiomyocyte dysfunction being the actual cause of the disease. Here, we describe a family with LVNC due to a novel missense mutation, pE96K, in the cardiac Troponin T gene (TNNT2). This novel mutation was identified in the index patient and all affected relatives, but not in 430 healthy control individuals. Mutations in known LVNC-associated genes G4.5, LDB3, DTNA, LMNA, MYH7 and MYBPC3 were excluded. To investigate the pathophysiological implications of this mutation, we generated transgenic mice expressing human wild-type cTnT (hcTNT) or a human troponin T harbouring the pE96K mutation (mut TNT). Transgenic animals were characterized by echocardiography, histology, and gene expression analysis. Transgenic mice carrying the pE96K mutation displayed decreased fractional shortening (39.7% ± 2.0%) compared to WT mice (51.7 ± 1.2%, p<0.001) and hcTNT mice (46.0% ± 2.6%, p<0.05). Consistently, the left enddiastolic diameter of mut TNT hearts was found significantly increased (mut TNT: 0.45 cm ± 0.01 cm; hcTNT: 0.41 cm ± 0.01 cm, P<0.01; WT: 0.40 cm ± 0.01 cm, p<0.001) Mut TNT mice also revealed a strong induction of marker genes of heart failure, including ANF (+522% ± 154%, p<0.05), BNP (+635% ± 100%, p<0.01), and β-MHC (1094% ± 293%, p<0.05). Remarkably, left-ventricular noncompaction was not observed in mut TNT hearts. In conclusion, familial cosegregation as well as the cardiomyopathy phenotype of mutant TNT mice strongly support a causal relationship of the pE96K mutation and disease in our index patient. In addition, our data suggest that a noncompaction phenotype is not required for the development of cardiomyopathy with contractile dysfunction in LVNC-associated mutations.