Mechanisms of Lamin A/C-mediated Cardiac Conduction Disorders

PROJECT SUMMARY The cardiac conduction system (CCS) is specialized in the generation and propagation of electrical impulses from the atria to the ventricles to produce a highly coordinated muscle contraction. Cardiac conduction disorders (CCDs) including sick sinus syndrome, atrioventricular block (AVB), and bundle branch block are common

arrhythmic disorders that impact the contraction of atria or ventricles. Cardiac pacing is the standard treatment for patients with symptomatic bradyarrhythmia resulting in implantation of over 600,000 pacemakers annually in US due to sinus node dysfunction (SND) or AVB. Currently, there is no alternative treatment for these patients.

Thus, understanding the molecular and cellular mechanisms leading to CCD may provide a foundation for new therapeutic strategies. A nonsense mutation (c.C673>T, p.R225>X) in lamin A/C (LMNA) identified in a kindred, was associated progressive CCD and atrial arrhythmias, preceding the development of cardiomyopathy and

heart failure. The mechanistic link between mutated lamin A/C and CCD is largely undetermined. Preliminary results suggest that the LMNA-R255X knockin mice develop CCD phenotype, similar to patient carriers of R225X mutation. The proposed work will elucidate the molecular mechanisms by which mutation in lamin A/C promote

CCD. Our study will establish the pathological function of lamin A/C in CCD development. The molecular pathways uncovered from this study will likely have a broader impact on our understanding of the molecular mechanisms of CCD in the general population.