By Charlotte Davison and Deborah Oakley
Tarantula spider proteins have helped scientists to understand for the first time how it is that genetic changes in heart muscle cause different forms of cardiomyopathy, one of the most common causes of heart failure and sudden death in otherwise healthy young people.
At first glance, hairy eight-legged spiders appear to have little in common with people. But some of the proteins that make up a spider’s muscles are similar to those in our own bodies, including our hearts. The researchers chose to study spider proteins because they allowed them to explore 3D protein structure in much greater detail than is currently possible with human models alone. In particular, studying the long, thin muscle fibres in spiders’ legs allowed them to see not only the structure of individual proteins, but also how these proteins interact with their neighbours.
The study is published today in the journal eLife, and was led by an international team including James Ware, a cardiologist at the MRC London Institute of Medical Sciences (LMS), based at Imperial College London, and others at Harvard Medical School and the Venezuelan Institute for Scientific Research. It describes the role of a protein called myosin, a key component of heart muscle. Mutations in the gene that produce this protein can cause different forms of cardiomyopathy, which affect around 1 in 250 people in the UK.
This study focuses on two types: dilated and hypertrophic cardiomyopathy. Dilated cardiomyopathy occurs when the heart muscle becomes thin and weak, and the heart chambers expand (dilate). In contrast, in hypertrophic cardiomyopathy, the muscle thickens and the chambers at the base of the heart become smaller. Both conditions affect the heart’s ability to pump blood around the body effectively. Symptoms include breathlessness, chest pain, palpitations, dizziness and loss of consciousness.
Ware and team were trying to understand why different mutations in the same gene could lead to these two cardiomyopathies, which in some ways appear as opposites – one with thick heart muscle that contracts too forcefully, the other with muscle that is thin and weak.
In heart muscle, chains of myosin proteins form thick muscle filaments, which sit side-by-side with thinner filaments, called actin. When a muscle contracts, the myosin fibres slide along the actin fibres to shorten the length of the muscle. It has been known that some cardiomyopathies are caused by mutations that interfere with myosin’s ability to bind to actin, changing the heart muscle contraction.
However, most previous studies have focused on single myosin molecules in isolation. In this study, the models of 3D protein structure allowed the researchers to see that as well as interacting with actin, myosin molecules interact with each other and work in pairs. These interactions are particularly important when the muscle relaxes, because they improve energy efficiency. The scientists found that mutations that cause dilated cardiomyopathy typically alter the parts of myosin which play a role in contraction. Most mutations that cause hypertrophic cardiomyopathy also affect contraction in this way, and additionally affect these newly identified interactions, interfering with the heart’s ability to relax.
According to Ware, these findings could help doctors to identify the exact cause of an individual’s condition by making genetic tests more accurate. “Today, genetic tests can identify the cause of these diseases in about one in three people. For other patients, the tests show a DNA mutation changes the protein, but we don’t know whether those changes are harmful or harmless. Our findings can be used immediately to refine this process and give doctors more confidence in saying whether a given DNA change causes disease,” says Ware. “We’ve also shown that over half of the mutations in myosin which cause hypertrophic cardiomyopathy lie in these critical binding regions. This shows the importance of mutations in this area.”
It’s useful to find the gene behind an individual’s disease because it can help to identify whether that patient’s children have inherited the condition. Relatives of cardiomyopathy patients often undergo regular and expensive heart tests. This new research findings should lead to an increase in the number of conclusive diagnoses. Those shown to have inherited the condition can be monitored and treated, perhaps even before the condition can be detected using conventional tests. Currently, if genetic testing is inconclusive, relatives usually receive life-long care in case they later develop the condition This new work means that those who do not have the faulty gene can be reassured and avoid costly and needless long-term follow-up.