Scientists link genetic spelling mistakes to sudden cardiac death

Scientists have found that the 'sudden' cardiac death condition related to high profile deaths or major medical episodes of sports stars including Fabrice Muamba, Christian Erikson and Mark-Vivian Foe has numerous linked gene variations, or "spelling mistakes", which highlights a potentially treatable vulnerability.

In a study published in Nature Communications today, a multi-disciplinary team of researchers, including scientists from the University of Birmingham, have uncovered new insights into how "spelling mistakes" in our DNA contribute to hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death worldwide.

"Spelling mistakes" in a protein called alpha-actinin-2 or ACTN2 have previously been identified for their role in the disease, but they have not addressed how these errors lead to cardiac arrest. This study found that 17 of the spelling mistakes in ACTN2 are linked to HCM, and that they affected the protein in different ways.

In the study, structural and cell biologists from the University of Birmingham, University of Oxford and the Research Campus Harwell teamed up to investigate 17 mistakes in ACTN2 using a range of experimental methods and found that they affect the protein in several different ways. Some errors made the protein less stable, more likely to clump together, or less able to interact with other molecules.

Researchers have also found that these spelling mistakes have different effects depending on where they are located within ACTN2. In particular, a critical region called the Actin Binding Domain (ABD), which helps ACTN2 interact with other parts of cells and is important for major cell processes, was identified as a key hotspot for changes caused by these spelling mistakes.

Corresponding author Katja Gehmlich, Professor of Molecular Cardiology at the University of Birmingham, commented: "Hypertrophic cardiomyopathy often affects otherwise fit and healthy individuals, and the effects of the condition can be devastating, as seen in the cases of high-profile footballers such as Mark-Vivian Foe who sadly died in competition. The findings will help us and other researchers worldwide to find potential ways to address these genetic weaknesses and better understand how these proteins are literally reshaping the heart of people with this condition."

Several of the experimental approaches used in this study are readily reproducible in other laboratories. We hope this framework will improve the interpretation of genetic test results for ACTN2-associated cardiomyopathies and could be adapted to study disease-causing genetic changes in other heart proteins."

Dr Fiyaz Mohammed, corresponding author and Lecturer, University of Birmingham

First author Maya Noureddine, and a PhD candidate at the University of Birmingham, remarked: "Inherited heart muscle diseases, known as cardiomyopathies, are often associated with sudden cardiac death. These conditions can be caused by genetic changes, like spelling mistakes in the DNA that affect essential heart proteins. However, it is challenging to determine whether a particular genetic change is responsible for disease, making it harder to interpret genetic test results for patients and their families.

"Using a range of laboratory techniques, our team has developed a systematic approach which helped identify which genetic changes are most likely to cause disease. We hope that these findings will ultimately support the development of new treatments for HCM and other cardiac diseases."

The findings also highlight the power of interdisciplinary collaboration, with experts from different fields combining their knowledge, technologies, and approaches to tackle a complex problem in cardiovascular disease.

The research is part of a wider set of studies by Professor Gehmlich and collaborators on hypertrophic cardiomyopathy and other genetic conditions that affect the heart.

Scientists have found that the 'sudden' cardiac death condition related to high profile deaths or major medical episodes of sports stars including Fabrice Muamba, Christian Erikson and Mark-Vivian Foe has numerous linked gene variations, or "spelling mistakes", which highlights a potentially treatable vulnerability.

In a study published in Nature Communications today, a multi-disciplinary team of researchers, including scientists from the University of Birmingham, have uncovered new insights into how "spelling mistakes" in our DNA contribute to hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death worldwide.

"Spelling mistakes" in a protein called alpha-actinin-2 or ACTN2 have previously been identified for their role in the disease, but they have not addressed how these errors lead to cardiac arrest. This study found that 17 of the spelling mistakes in ACTN2 are linked to HCM, and that they affected the protein in different ways.

In the study, structural and cell biologists from the University of Birmingham, University of Oxford and the Research Campus Harwell teamed up to investigate 17 mistakes in ACTN2 using a range of experimental methods and found that they affect the protein in several different ways. Some errors made the protein less stable, more likely to clump together, or less able to interact with other molecules.

Researchers have also found that these spelling mistakes have different effects depending on where they are located within ACTN2. In particular, a critical region called the Actin Binding Domain (ABD), which helps ACTN2 interact with other parts of cells and is important for major cell processes, was identified as a key hotspot for changes caused by these spelling mistakes.

Corresponding author Katja Gehmlich, Professor of Molecular Cardiology at the University of Birmingham, commented: "Hypertrophic cardiomyopathy often affects otherwise fit and healthy individuals, and the effects of the condition can be devastating, as seen in the cases of high-profile footballers such as Mark-Vivian Foe who sadly died in competition. The findings will help us and other researchers worldwide to find potential ways to address these genetic weaknesses and better understand how these proteins are literally reshaping the heart of people with this condition."

Dr Fiyaz Mohammed, corresponding author and Lecturer at the University of Birmingham stated: "Several of the experimental approaches used in this study are readily reproducible in other laboratories. We hope this framework will improve the interpretation of genetic test results for ACTN2-associated cardiomyopathies and could be adapted to study disease-causing genetic changes in other heart proteins."

First author Maya Noureddine, and a PhD candidate at the University of Birmingham, remarked: "Inherited heart muscle diseases, known as cardiomyopathies, are often associated with sudden cardiac death. These conditions can be caused by genetic changes, like spelling mistakes in the DNA that affect essential heart proteins. However, it is challenging to determine whether a particular genetic change is responsible for disease, making it harder to interpret genetic test results for patients and their families.

"Using a range of laboratory techniques, our team has developed a systematic approach which helped identify which genetic changes are most likely to cause disease. We hope that these findings will ultimately support the development of new treatments for HCM and other cardiac diseases."

The findings also highlight the power of interdisciplinary collaboration, with experts from different fields combining their knowledge, technologies, and approaches to tackle a complex problem in cardiovascular disease.

The research is part of a wider set of studies by Professor Gehmlich and collaborators on hypertrophic cardiomyopathy and other genetic conditions that affect the heart.