Scientists from the University of Pennsylvania have discovered how mutations in the LMNA gene cause a congenital form of dilated cardiomyopathy, a serious heart condition that can be fatal.
The researchers found that LMNA gene mutations have a particularly adverse effect on cardiac muscle cells compared to other cell types, causing abnormal activation of a range of genes that are normally switched off in these cells and inducing reduced mechanical elasticity.
Dilated cardiomyopathy occurs when the heart becomes enlarged and as a result cannot pump blood effectively around the body. It impacts around 1 in 2500 people and has a 5-year survival rate of around 50%. It can occur due to a number of different causes including infections, exposure to toxic substances, and as a symptom of other medical conditions, but 25-35% of cases are due to inherited genetic mutations.
Mutations in a variety of different genes can cause inherited dilated cardiomyopathy, but variants in the LMNA gene are the second most common case in familial cases.
The LMNA protein is located on the inner wall of the nucleus of cells where the chromosomes are stored. It forms a structure called the lamina that touches parts of the DNA and is thought to help regulate gene activity via these interactions.
However, while this protein is found in most cells, mutations in the gene only appear to cause a few specific diseases. Including dilated cardiomyopathy, mutations can cause a type of premature aging syndrome known as progeria and two forms of muscular dystrophy.
To try and understand why these mutations adversely affect the heart, Rajan Jain, M.D., an assistant professor at the Perelman School of Medicine, and colleagues took healthy human induced pluripotent stem cells (hiPSCs) and used CRISPR gene editing techniques to induce LMNA mutations known to cause this form of cardiomyopathy. They then used molecular switches to turn some of these cells into cardiac muscle cells, or cardiomyocytes, and some into liver and fat cells for comparison purposes.
As reported in the journal Cell Stem Cell, in the cardiomyocytes the cell lamina did not interact with the genome in a normal way leading to abnormal gene expression of various genes in these cells – many genes usually silent in these cells had become abnormally activated. These changes caused the cardiac cells to start displaying some characteristics of other cell types.
The cardiomyocytes had also lost a significant amount of mechanical elasticity, which normally allows them to stretch and contract regularly.
Notably, the same could not be seen in the liver and fat cells with LMNA mutations, which had an almost normal lamina, no notable disruptions to gene expression and normal elasticity.
“The findings reveal the likely importance of the nuclear lamina in regulating cell identity and the physical organization of the genome,” commented Jain, who co-led the work with Kiran Musunuru, M.D., Ph.D., a professor at the Perelman School of Medicine.
“This also opens up new avenues of research that could one day lead to the successful treatment or prevention of LMNA-mutations and related disorders.”
The team are now trying to understand these cellular abnormalities better and assess how the disruption to the lamina in the cardiomyocytes impacts the chromatin and causes changes in gene expression.
“Further work along these lines should enable us to predict how LMNA mutations will manifest in individual patients, and ultimately we may be able to intervene with drugs to correct the genome disorganization that these mutations cause,” said Musunuru.
