Researchers uncover how gene that increases risk of genetic heart disease works, paving way for new treatments

Researchers have discovered how a gene that increases the risk of developing genetic heart disease functions, paving the way for new treatments.

The study, led by Murdoch Children’s Research Institute and published in Nature Cardiovascular Research, 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.

Heart disease is the leading cause of death worldwide. 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.

Dr James McNamaraDr James McNamara said the disease was often caused by genetic mutations that impacted heart muscle function. The gene, ALPK3 that controls the heart’s capacity to beat normally had been shown to increase cardiomyopathy risk when mutated, he said.

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

“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.”

The research 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.

Murdoch Children’s 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,” he 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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