Grant: Project Grant

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that can cause sudden death as its first symptom. It tragically shortens the lives of healthy young people, with men affected worse than women. 50% of ARVC men will die by age 40, and 80% by 50 (5% and 20% of women). Genes are messages written in a DNA alphabet that build proteins. Proteins are the building blocks of the cells from which we are all made. A mistake in a gene can disrupt the protein causing serious disease. ARVC in Newfoundland is caused by a DNA spelling mistake in a gene called TMEM43. This mutation was discovered in Newfoundland. Men and women both inherit the TMEM43 gene mutation, and pass it on to 50% of their children. Thus, ARVC is known as "The Newfoundland curse". Although all people with the TMEM43 gene mutation will get ARVC, it is not the same severity in everyone. We know nothing about what this gene change does to heart cells. We do not know why women are protected compared to men. We do not know why some need a cardiac transplant, and others do not. We have a dedicated group of families invested in helping with our research. We have collected skin samples from affected and unaffected family members and 'reprogrammed' their skin cells into induced pluripotent stem cells (iPSC). These iPSCs can become any cell type, including beating heart cells. We can then investigate how ARVC heart cells are different than their unaffected siblings. We can "repair" the DNA in these cells using CRISPR-Cas9 technology. The large families mean we can access subjects with severe forms of ARVC, and less severe forms, and access their gene negative brothers and sisters as controls. ARVC caused by this mutation is seen worldwide. This research proposal will allow us to understand basic ARVC biology, which may lead to new therapies based on understanding the causes of the variation in disease presentation we see, leading to true precision medicine.