Mutations of the Lamina A/C gene, a fundamental protein in the nuclear envelope of the cell, cause cardiomyopathy, a heart muscle disease associated with heart dilation and impaired function, and are associated with conduction disorders, arrhythmia and sudden death.

The mechanism was identified by a study of the Institute of Genetic and Biomedical Research of the National Research Council (CNR-Irgb) and Humanitas and the research was published in the journal Nature Communications.

As Dr. Elisa Di Pasquale, a researcher at the Institute of Genetic and Biomedical Research of the National Research Council (CNR-Irgb) and Humanitas, explains: “In our study we used in vitro cardiac models, generated by a process of reprogramming the skin cells of patients carrying the K219T mutation into iPSC cells (from the English Induced Pluripotent Stem Cells), and their subsequent differentiation into cardiomyocytes, the heart cells underlying the contractile properties of the heart muscle. The iPSC cells, first described in 2006 by Nobel Prize winner Shinya Yamanaka, have revolutionised the approach to the study of diseases and have allowed us to investigate the functional and molecular mechanisms underlying lamine-dependent cardiomyopathy”.

The study

Using these patient-specific models and the new CRISPR-Cas9 gene correction techniques, the team of researchers from Cnr-Irgb and the Clinical Institute Humanitas identified the specific functional defects induced by the K219T mutation of Lamina A/C and outlined the mechanisms responsible for them. In fact, it emerged that the mutated cardiomyocytes have reduced quantities of sodium currents, which are essential for the correct transmission of the electrical impulse of the heart muscle. This predisposes to the onset of arrhythmias that often occur in patients carrying this mutation or similar. It has also been demonstrated the role that the lamina plays in epigenetically regulating the expression of the gene of the sodium channel (SCN5A), the protein through which the sodium current passes, therefore of fundamental importance for the electrical excitability of cardiac cells.

Mutations in the lamina gene therefore lead to a reduced expression of the sodium channel gene, which in turn determines the propensity of the diseased heart cell to generate rhythm disturbances and arrhythmias.

The results of this research therefore improve the understanding of the diseases caused by Lamina A/C and identify in the SCN5A sodium channel gene a potential molecular target for a therapy of conduction disorders in these patients. In the future, it will be possible to use diseased cells generated by the Yamanaka method to experiment with new molecules that cure the disease in vitro, before moving on to human experimentation.

The study, which is funded by the Ministry of Health, the Ministry of Education, Universities and Research, the European Research Council, the CNR’s Interomics Flag Project and the “Io Merito” project of the 5×1000 of Humanitas, is the result of the collaboration between the research groups of Elisa Di Pasquale and Gianluigi Condorelli, both related to the CNR-Irgb and Irccs Humanitas Clinical Institute, and the collaboration of researchers and doctors working in Italy and abroad (University of Parma, University of Washington, University of Verona, Cardiovascular Department of the “Ospedali Riuniti” and University of Trieste).