Novel lamin AC mutations and their expression in the cardiac tissue of end-stage dilated cardiomyopathy patients

Abstract

Dilated cardiomyopathy (DCM) is a cardiac muscle disorder characterized by ventricular dilatation and impaired systolic function. LMNA, one of fifteen autosomal genes implicated in this disease, encodes for two alternatively spliced nuclear intermediate filaments proteins, lamins A and C. Two novel missense mutations, D192G and R541 S, were identified in highly conserved regions of the LMNA gene. Electron micrographs of cardiac tissue containing the D192G mutation demonstrated dramatic morphologic alterations of the nucleus. By contrast, cardiac samples from the R541 S carrier were almost indistinguishable from those of transplanted DCM patients without LMNA mutations. Expression levels of total LMNA mRNA in this individual were comparable to those found in end-stage DCM patients without LMNA mutations. Moreover, the mutated allele was expressed in the heart tissue of this patient. Functional studies to determine the impact of these mutations on cellular models are ongoing.