Abstract 12661: A Novel Mutation in a Lamin A/C Gene Associated with Dilated Cardiomyopathy, Degeneration of Cardiac Conduction System, and Altered Gene Expression
Background: Lamins A and C form a nuclear envelope-associated lattice as the main structural components of the nuclear lamina and play an important role for chromatin structure, regulation of gene expression, and protein localization and degradation. Mutations in LMNA encoding lamin A/C are associated with dilated cardiomyopathy and conduction disease.
Methods and Results: Screening for mutations in LMNA was performed in families affected by dilated cardiomyopathy and conduction disease requiring pacemaker implantation. The effects of an LMNA mutation on histology and gene expression profiles in heart were studied. We identified a novel missense mutation F237C in exon 4 of LMNA. The proband was a 55-year-old man with sinus node dysfunction, complete atrioventricular block, and dilated cardiomyopathy. In his family, multiple members had pacemaker implantation and dilated cardiomyopathy. He received his pacemaker 6 years prior to the development of dilated cardiomyopathy. He died from heart failure despite cardiac resynchronization therapy. Autopsy revealed that myocytes were depleted, extensive fibrosis, and that remaining myocytes were hypertrophied, wavy, and fragmented with bizarre nuclei and nuclear lobulation in both atria and ventricles. Notably, marked myofibrillar degeneration of myocytes with fatty replacement was found in the sinoatrial and atrioventricular nodes. We profiled gene expression in the left ventricle in the proband using microarray analysis, compared to the left ventricle from an adult male with end-stage dilated cardiomyopathy who was negative for mutations in LMNA. The microarray analyses revealed that the F237C LMNA mutation was associated with the remarkable changes of gene expression including the upregulation (more than 10 times) of 319 genes and the downregulation (less than one tenth) of 833 genes among 54,645 genes tested.
Conclusions: We identified a novel mutation in LMNA associated with dilated cardiomyopathy, sinus node dysfunction, and conduction disease, and found the marked changes of histology and gene expression in heart. Our data provide a mechanism underlying a range of unusual cardiac phenotypes caused by LMNA mutations.
- © 2011 by American Heart Association, Inc.