Explained: the gene mutation that causes heart disease

A research team led by the Murdoch Children’s Research Institute (MCRI) has revealed a new pathway for how children and adults develop cardiomyopathy, a group of diseases that affect the heart’s ability to pump blood around the body. Their study, published in the journal Nature Cardiovascular Research, has the potential to pave the way for new treatments.

Patients with cardiomyopathy, a form of heart disease affecting about 30 million people, are at greater risk of heart failure and death — and treatment options are limited. As explained by MCRI’s Dr James McNamara, the disease is often caused by genetic mutations that impacted heart muscle function. The gene ALPK3, which controls the heart’s capacity to beat normally, has been shown to increase cardiomyopathy risk when mutated, he said.

“Mutations in this gene can cause very severe and sometimes fatal cardiomyopathy in children,” McNamara said. But it has been unknown what ALPK3 does in the heart and how its mutation causes disease.

The researchers used a combination of genetically engineered human stem cell models and mice to uncover the function of ALPK3 in the heart and to understand how it causes disease when mutated. McNamara said, “Our research is the first to show how ALPK3 directly controls the function of contractile proteins in the heart that drive normal pumping.

“We found that ALPK3 links these contractile proteins to quality control systems and that its mutation hinders this link, causing a build-up of damaged proteins. This impairs the heart’s ability to pump blood to the rest of the body, causing breathlessness, swollen legs and feet and extreme fatigue and, if left untreated, can lead to heart failure.”

MCRI Associate Professor David Elliott said the findings could lead to new drug discoveries to treat cardiomyopathy.

“With limited treatment options for patients, new targeted therapies are desperately needed,” Elliott said. “But armed with a greater understanding of how this gene works, and by engineering stem cells in the lab to model genetic cardiomyopathy, we can screen for new drugs and identify disease mechanisms. This could lead to new targeted treatments that restore heart function.”

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