Pleiotropy in LMNA-associated Arrhythmogenic Cardiomyopathy

可疑家族性心肌病和致瘤性心肌病的基因检测 (ACM)正在成为评估受影响个体的护理标准。所得 遗传信息能够确定病因，提供对预后的见解， 确定有遗传病风险的家庭成员。这代表了第一步 为心脏遗传学提供精准医学的努力这些进步暴露了 成功转化为精确疗法的挑战。一个目标是基因型特异性 治疗受影响的个人超出标准心肌病治疗。级联 对家庭成员的遗传筛查发现了越来越多的突变携带者， 大部分处于早期甚至临床前阶段。除了监测和治疗早期 虽然这些国家没有任何症状，但在采取预防措施方面却没有什么可提供的。这是一 机会干预，因为突变基因表达将在出生时开始， 在明显的疾病之前积累多年的影响。为了有效地解决这一群体的问题， 我们必须更好地理解：1）导致疾病的早期生物扰动，2）是否 不同类型的突变（即使在同一基因内）通过变量引起疾病 机制，以及3）哪些心脏细胞类型最早受到影响。致病性突变， LMNA基因（编码核纤层蛋白A/C蛋白）导致进行性心肌病， 明显心律失常有相当大的多效性和表型变异。LMNA是 在分化的组织中广泛表达，包括在所有心脏细胞类型（肌细胞， 成纤维细胞、巨噬细胞、内皮细胞）。不同的突变可能会影响不同的器官， 高度可变的呈现。然而，在一个特定的家庭中，这些突变似乎是真实的， (age发作的时间、进展的速率、心律失常的程度等）。通过我们的基因 临床上，我们招募了具有不同LMNA突变的家庭，并产生了诱导的LMNA突变。 来自外周血单核细胞的多能干细胞（IPSC）用于建立LMNA心肌病模型 机制等我们的初步数据表明，不同的LMNA突变与 可变表型，包括基因表达、核形态、电生理学、细胞 迁移和细胞死亡。此外，这些差异延伸到非肌细胞心肌细胞 （心脏成纤维细胞）。我们的假设是：A）LMNA中的特定突变导致ACM， 不同的分子途径，B）不同的LMNA突变影响不同的心肌细胞类型 导致疾病，和C）LMNA突变特异性早期分子扰动将影响 旨在疾病预防的治疗反应。

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.