Gene mutations in a protein called titin affect the heart function of healthy people, report researchers. The mutations were thought to affect only patients with dilated cardiomyopathy, one of the most common forms of inherited heart disease.

Gene Mutation Hearts
Gene Mutation By Kenshinb (Own work) [CC BY-SA 3.0], via Wikimedia Commons
Gene Mutation

The finding may help scientists to understand a paradox: about 1 percent of people carry this genetic mutation with no apparent effect.

The key, the team now believes, is that the hearts of such people may be “primed to fail” if they suffer a second hit, whether genetic or environmental. This could mean that there are about 35 million people in this position globally. The paper appears in the journal Nature Genetics.

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Titin is the largest protein in the human body that causes dilated cardiomyopathy, a condition in which the heart muscle becomes weakened, enlarged, and cannot pump blood efficiently. Dilated cardiomyopathy is a type of inherited cardiac condition and affects about 1 in 250 people worldwide.

“Our next step is to find out the specific genetic factors or environmental triggers, such as alcohol or viral infection, that may put certain people with titin mutations at risk of heart failure.”

The researchers studied the effects of titin gene mutations in 2,495 patients with dilated cardiomyopathy. They also generated two rat models to understand the impact of these mutations on the molecular level and heart function. In addition, cardiac gene sequencing tests were performed in 1,409 healthy volunteers, coupled with 2D and 3D cardiac magnetic resonance imaging (MRI) that gave high-resolution information on the heart size and shape of the study subjects.

“We could directly show the impact of the mutations on the titin protein production which has an impact on the heart,” says first author Sebastian Schäfer, assistant professor and senior research fellow at the National Heart Centre Singapore.

“Even though the heart appears healthy initially, it reacts to this genetic stress on many levels such as changes to its gene expression and energy source. The heart can compensate and its cardiac function remains fine until an additional stressor occurs. That’s when the heart fails, as it no longer has the capacity to react the same way a healthy heart does.”

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Professor Stuart Cook, professor of cardiovascular medicine at the SingHealth Duke-NUS Academic Medical Centre and co-senior author of the paper, elaborates: “We now know that the heart of a healthy individual with titin gene mutation lives in a compensated state and that the main heart pumping chamber is slightly bigger.

“Our next step is to find out the specific genetic factors or environmental triggers, such as alcohol or viral infection, that may put certain people with titin mutations at risk of heart failure.”

The National Heart Centre Singapore led the work in collaboration with Duke-NUS Medical School, Medical Research Council Clinical Sciences Centre, Imperial College London, and Max Delbrück Center for Molecular Medicine in the Helmholtz Association.

The Tanoto Foundation, National Medical Research Council Singapore, SingHealth Duke-NUS Institute of Precision Medicine, Medical Research Council Clinical Sciences Centre UK, NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield NHS Foundation Trust, and Imperial College London and British Heart Foundation UK, among others, funded the work.

Source: Duke-NUS

Original Study DOI: 10.1038/ng.3719

by National University of Singapore