Scientists have discovered that the condition of “sudden” cardiac death, which has been linked to high-profile deaths and critical medical episodes in sports stars such as Fabrice Muamba, Christian Ericsson and Marc Vivian Fau, is associated with a number of genetic mutations, or “mispellings,” highlighting potentially treatable vulnerabilities.
In a study published today in Nature Communications, a multidisciplinary team of researchers, including scientists from the University of Birmingham, revealed new insights into how ‘mispellings’ in DNA contribute to hypertrophic cardiomyopathy (HCM), the leading cause of sudden cardiac death worldwide.
It was previously identified that misspellings of a protein called alpha-actinin-2, or ACTN2, were involved in the disease, but there was no mention of how these mistakes could lead to cardiac arrest. The study found that 17 of the misspellings of ACTN2 were associated with HCM and that they affected the protein in different ways.
In this study, structural and cell biologists from the University of Birmingham, the University of Oxford, and the Harwell Research Campus collaborated to investigate 17 mistakes in ACTN2 using a variety of experimental methods and found that they affect the protein in several different ways. Some errors can reduce the stability of proteins, making them more prone to aggregation or less likely to interact with other molecules.
The researchers also found that these misspellings had different effects depending on where they were located within ACTN2. In particular, a critical region called the actin-binding domain (ABD), which helps ACTN2 interact with other parts of the cell and is important for key cellular processes, was identified as a key hotspot for changes caused by these misspellings.
Corresponding author Katja Gamelich, Professor of Molecular Cardiology at the University of Birmingham, said: ‘Hypertrophic cardiomyopathy often affects otherwise fit and healthy people, as seen in famous footballers such as Marc Vivian Faure who sadly died while playing. “As such, the effects of this condition can be devastating. This discovery will help us and researchers around the world find potential ways to address these genetic weaknesses and better understand how these proteins work.” It literally reshapes the minds of people with this condition. ”
Some of the experimental approaches used in this study can be easily replicated in other laboratories. We hope that this framework will improve the interpretation of genetic test results for ACTN2-related cardiomyopathy and can be applied to the study of disease-causing genetic changes in other cardiac proteins. ”
Dr Fiyaz Mohammed, corresponding author and lecturer, University of Birmingham
Maya Noureddin, lead author and PhD candidate at the University of Birmingham, said: ‘Inherited heart muscle diseases known as cardiomyopathy are often associated with sudden cardiac death. “It can be caused by a genetic change, such as P. permis. However, it is difficult to determine whether a particular genetic change is the cause of the disease, and genetic test results are difficult for patients and their families to interpret.”
“Using a variety of testing techniques, our team has developed a systematic approach to help identify which genetic changes are most likely to cause disease. We hope that these discoveries will ultimately support the development of new treatments for HCM and other heart diseases.”
The findings also highlight the power of interdisciplinary collaboration, where experts from different fields combine their knowledge, skills, and approaches to tackle the complex problems of cardiovascular disease.
The study is part of a broader study by Professor Gamelich and colleagues into hypertrophic cardiomyopathy and other genetic diseases that affect the heart.
Scientists have discovered that the condition of “sudden” cardiac death, which has been linked to high-profile deaths and critical medical episodes in sports stars such as Fabrice Muamba, Christian Ericsson and Marc Vivian Fau, is associated with a number of genetic mutations, or “mispellings,” highlighting potentially treatable vulnerabilities.
In a study published today in Nature Communications, a multidisciplinary team of researchers, including scientists from the University of Birmingham, revealed new insights into how ‘mispellings’ in DNA contribute to hypertrophic cardiomyopathy (HCM), the leading cause of sudden cardiac death worldwide.
It was previously identified that misspellings of a protein called alpha-actinin-2, or ACTN2, were involved in the disease, but there was no mention of how these mistakes could lead to cardiac arrest. The study found that 17 of the misspellings of ACTN2 were associated with HCM and that they affected the protein in different ways.
In this study, structural and cell biologists from the University of Birmingham, the University of Oxford, and the Harwell Research Campus collaborated to investigate 17 mistakes in ACTN2 using a variety of experimental methods and found that they affect the protein in several different ways. Some errors can reduce the stability of proteins, making them more prone to aggregation or less likely to interact with other molecules.
The researchers also found that these misspellings had different effects depending on where they were located within ACTN2. In particular, a critical region called the actin-binding domain (ABD), which helps ACTN2 interact with other parts of the cell and is important for key cellular processes, was identified as a key hotspot for changes caused by these misspellings.
Corresponding author Katja Gamelich, Professor of Molecular Cardiology at the University of Birmingham, said: ‘Hypertrophic cardiomyopathy often affects otherwise fit and healthy people, as seen in famous footballers such as Marc Vivian Faure who sadly died while playing. “As such, the effects of this condition can be devastating. This discovery will help us and researchers around the world find potential ways to address these genetic weaknesses and better understand how these proteins work.” It literally reshapes the minds of people with this condition. ”
Dr Fiyaz Mohammed, corresponding author and lecturer at the University of Birmingham, said: “Some of the experimental approaches used in this study are easily reproducible in other laboratories. We hope that this framework will improve the interpretation of genetic test results for ACTN2-related cardiomyopathy and can be applied to the study of disease-causing genetic changes in other cardiac proteins.”
Maya Noureddin, lead author and PhD candidate at the University of Birmingham, said: ‘Inherited heart muscle diseases known as cardiomyopathy are often associated with sudden cardiac death. “It can be caused by genetic changes, such as misspellings. But it can be difficult to determine whether a particular genetic change is causing the disease, and it can be difficult for patients and their families to interpret genetic test results.”
“Using a variety of testing techniques, our team has developed a systematic approach to help identify which genetic changes are most likely to cause disease. We hope that these discoveries will ultimately support the development of new treatments for HCM and other heart diseases.”
The findings also highlight the power of interdisciplinary collaboration, where experts from different fields combine their knowledge, skills, and approaches to tackle the complex problems of cardiovascular disease.
The study is part of a broader study by Professor Gamelich and colleagues into hypertrophic cardiomyopathy and other genetic diseases that affect the heart.
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Reference magazines:
Noureddin, M. others. (2026). Comprehensive biophysical and structural profiling of α-actinin-2 mutants reveals mechanistic diversity of hypertrophic cardiomyopathy. Nature Communications. DOI: 10.1038/s41467-026-75392-z. https://www.nature.com/articles/s41467-026-75392-z
