Abstract 2819: Mutations Of Presenilin Genes In Familial Dilated Cardiomyopathy And Heart Failure

Dilated cardiomyopathy (DCM) is a myocardial degenerative disease and is frequently familial. Its molecular pathogenesis remains to be elucidated. Accumulating evidences suggest common mechanisms underlying the tissue degeneration in different organs. Presenilins, highly expressed in hearts and critical to cardiovascular development, implicate neurodegeneration in Alzheimer’s disease. We therefore postulated that genetic defects in presenilins may also cause myocardial degeneration and consequently dilated cardiomyopathy.Clinical evaluations were conducted on132 independent kindreds of familial DCM and 183 patients with idiopathic DCM. Presenilin 1 and 2 were sequenced for mutations in those index patients and their family members when indicated. The histopathological studies were performed on cardiac tissues. Primary fibroblast cell lines from patients were utilized to interrogate intracellular calcium signaling.Two distinct mutations, a novel missense mutation of Presenilin1 and a single residue substitution in presenilin 2, were identified in three unrelated multi-generation families. The mutations altered two highly conserved amino acids and were present in all clinically affected subjects, but none of 309 controls. The family with preseniln 1 mutation featured complete penetrance and progressive heart failure. Two other families carrying presenilin 2 mutation showed incomplete penetrance and mild cardiomyopthy and other cardiac abnormalities. Myocardium pathology is consistent with idiopathic DCM and no positive staining for amyloid or other protein aggresome substrates was observed in an explanted heart. Intracellular calcium signaling was altered in patients’ fibroblasts. In conclusion, we have for the first time linked genetic defects of presenilins with dilated cardiomyopathy and heart failure. The finding suggests a shared molecular mechanism for tissue degeneration of distinctive origins of either cardiac myocytes or neurons.