Pleiotropy in LMNA-associated Arrhythmogenic Cardiomyopathy

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Genetic testing for suspected familial cardiomyopathy and arrhythmogenic cardiomyopathy (ACM) is becoming standard of care in the evaluation of affected individuals. The resulting genetic information enables determination of etiology, provides insights on prognosis, and identification of family members at-risk for inherited disease. This represents a first step towards delivering Precision Medicine in cardio-genetics. Such advancements have exposed unmet challenges for successful translation to precise therapies. One goal is genotype-specific treatments for the affected individuals beyond standard cardiomyopathy therapy. Cascade genetic screening of family members identifies a growing population of mutation carriers who largely are in early- or even pre-clinical stages. Besides surveillance and treatment of early symptoms, there is not much to offer them in terms of pre-emptive measures. This is an opportunity intervene since mutant gene expression will begin at birth and exert incremental effects that accumulate over may years prior to overt disease. To effectively address this cohort we must better understand: 1) early biological perturbations that lead to disease, 2) whether different types of mutations (even within the same gene) cause disease by variable mechanisms, and 3) which cardiac cell-types are affected earliest. Pathogenic mutations in the LMNA gene (encoding the lamin A/C protein) cause a progressive cardiomyopathy with prominent arrythmias. There is considerable pleiotropy and phenotypic variability. LMNA is widely expressed in differentiated tissues, including in all cardiac cell types (myocytes, fibroblasts, macrophages, endothelial cells). Different mutations may affect different organs with highly variable presentation. Within a given family however, the mutations appear to breed true (age of onset, rate of progression, degree of arrhythmia, etc.). Through our Cardio-genetics clinic we have recruited families with different LMNA mutations and have generated Induced Pluripotent Stem Cells (IPSC) from peripheral blood monocytes to model LMNA cardiomyopathy mechanisms. Our preliminary data indicate that different LMNA mutations associated with variable phenotypes including, gene expression, nuclear morphology, electrophysiology, cell migration, and cell death. Furthermore, these differences extend into non-myocyte cardiac cells (cardiac fibroblasts). Our hypotheses are that: A) specific mutations in LMNA lead to ACM via different molecular routes, B) different LMNA mutations impact different cardiac cell-types leading to disease, and C) LMNA mutation-specific early molecular perturbations will affect therapeutic responses aimed at disease pre-emption.