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Abstract
Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease, but the mechanisms making cardiac tissues uniquely vulnerable to the mutations remain largely unknown. Further, patients with LMNA mutations have highly variable presentation of heart disease progression and type. In vitro patient-specific experiments could provide a powerful platform for studying this phenomenon, but the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity and function thus complicating the interpretation of the results of any single experiment. We hypothesized that integrating single cell RNA sequencing (scRNA-seq) with analysis of the tissue architecture and contractile function would elucidate some of the probable mechanisms. To test this, we investigated five iPSC-CM lines, three controls and two patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues had significantly weaker stress generation potential than control iPSC-CM tissues demonstrating the viability of our in vitro approach. Through scRNA-seq, differentially expressed genes between control and patient lines were identified. Some of these genes, linked to quantitative structural and functional changes, were cardiac specific, explaining the targeted nature of the disease progression seen in patients. The results of this work demonstrate the utility of combining in vitro tools in exploring heart disease mechanics.
Highlights
Heart disease, which impacts more than 80 million people just in the USA,[41] is caused by a variety of factors including genetic mutations.[16,27] Often the mechanisms by which these mutations cause heart disease are not known,[29,31] and the mutation is identified purely by studying the genes of large families with a history of heart disease.[6,45,72,73] Identifying the culprit gene provides relief to the family members who do not have the mutation, but does not usually help the individuals with the mutation
We present the results of a study of a Lamin A/C (LMNA) splice site mutation (c.3572A>G),[72] which causes inherited heart disease in patients (Table 1)
Here we demonstrate for this mutation that it is possible to construct an in vitro platform that has pathology in patientspecific heart tissues when compared to a negative control
Summary
Heart disease, which impacts more than 80 million people just in the USA,[41] is caused by a variety of factors including genetic mutations.[16,27] Often the mechanisms by which these mutations cause heart disease are not known,[29,31] and the mutation is identified purely by studying the genes of large families with a history of heart disease.[6,45,72,73] Identifying the culprit gene provides relief to the family members who do not have the mutation, but does not usually help the individuals with the mutation. To truly impact such patients, it is essential to elucidate the mechanism linking the mutation to the pathology Such studies are often possible only with an in vitro platform
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