Dilated cardiomyopathy, a common cause of heart failure, can be attributed to defects in any of more than 40 different genes. A new study reveals that defects in the gene that encodes the human body\u2019s largest protein, the muscle protein titin, are responsible for more cases of the disease than are caused by all other known mutations. <\/p>\n
In a study of nearly 800 people, researchers found unique mutations that truncate titin in 22% of people with dilated cardiomyopathy. Researchers have had a difficult time learning exactly how Titin mutations lead to the disease because of the high expense and technical difficulty in sequencing the unusually large gene. <\/p>\n
\u201cIt wasn\u2019t that we weren\u2019t aware that titin caused disease\u2014we were. The problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.\u201d
Christine E. Seidman <\/p>\n
In dilated cardiomyopathy, the heart blows up like a balloon. The stretched-out walls of muscle aren\u2019t able to contract effectively, so the heart starts to fail at its job of pumping blood around the body. Deprived of oxygen and nutrients, the patient gets short of breath easily and retains fluid. Eventually, the only option is a heart transplant. <\/p>\n
Dilated cardiomyopathy tends to run in families, so Christine Seidman, a Howard Hughes Medical Institute (HHMI) investigator at Brigham and Women\u2019s Hospital in Boston, and her team have looked for\u2014and found\u2014several genes associated with the disease. But still, \u201cwe weren\u2019t getting very far,\u201d she says. Every gene was a step forward, but each gene still only accounted for a small percentage of cases of dilated cardiomyopathy. \u201cWe had the sense that maybe we\u2019re missing something,\u201d Seidman says. \u201cWe took a step back a few years ago to say, \u2018What are we missing?\u2019\u201d <\/p>\n
Seidman and her colleagues realized that, over the years, they had found several hints that problems with the titin protein could cause dilated cardiomyopathy. Titin is part of the sarcomere, the unit of muscle that contracts. Titin helps assemble the sarcomere as the heart muscle grows and also plays a role in muscle contractions. <\/p>\n
But no one had ever organized a big study on titin. \u201cIt wasn\u2019t that we weren\u2019t aware that titin caused disease\u2014we were,\u201d Seidman says. \u201cThe problem was that the technology was not sufficiently robust to allow comprehensive analysis of that gene in a large collection of patients.\u201d <\/p>\n
The problem, in short, was that titin is enormous and sequencing was expensive. The protein is the longest humans make, some 33,000 amino acids stuck end to end. By comparison, the motor protein myosin has about 2,000 amino acids and Lamin A\/C, a nuclear membrane protein that is also associated with dilated cardiomyopathy, only has about 675 amino acids. It was just too expensive to sequence big genes in a big group of people, so researchers had passed it over. <\/p>\n
In the last decade, the technology has changed. Next-generation sequencing techniques have made it relatively cheap and easy to sequence long stretches of DNA fast. In a study published February 16, 2012, in The New England Journal of Medicine, Seidman and her colleagues sequenced the gene TTN, which codes for titin, in 312 people with dilated cardiomyopathy. They found 72 mutations that made incomplete forms of titin. Together, these explained about a quarter of the cases of dilated cardiomyopathy that run in families and weren\u2019t caused by something else, like cardiovascular disease. That\u2019s more than all the other genes they\u2019d found put together. <\/p>\n
Seidman, her husband Jon Seidman, and their colleagues at Harvard Medical School started out with a smaller group, 92 people with dilated cardiomyopathy who came to Brigham and Women\u2019s Hospital. When they began their study, the team expected to find that TTN was yet another gene that accounted for a small number of cases of the disease. They were shocked by what they found: 28 percent of the people had dramatic mutations in the DNA encoding titin, the kind that mean the protein wouldn\u2019t be fully made. <\/p>\n
When they did their initial analysis of that data, Seidman recalls, \u201cwe said, \u2018this is too good to be true.\u2019 \u201cThat\u2019s why we went and got more cohorts.\u201d They then sequenced the TTN gene in 71 people with dilated cardiomyopathy from Imperial College in the UK who had been evaluated for heart transplants\u2014they were, on average, much sicker than the Boston patients\u2014and 149 other people with dilated cardiomyopathy from the University of Colorado and the University of Trieste in Italy. The team also sequenced the gene in 231 people with another form of cardiomyopathy recruited at the Mayo Clinic and 249 controls who did not have cardiomyopathy. Stuart Cook at Imperial College, Luisa Mestroni and Matthew Taylor at the University of Colorado, and Michael Ackerman at the Mayo Clinic led the efforts at the collaborating institutions. The data from that larger analysis confirmed what their initial study had hinted: mutations in the TTN gene are the most common known genetic cause of dilated cardiomyopathy. <\/p>\n
Seidman hopes someday doctors will use this information to identify people who are likely to develop dilated cardiomyopathy before they get sick. As sequencing continues to get cheaper, it should eventually be possible for individuals to find out if they have a mutation associated with dilated cardiomyopathy. Then they could start taking drugs that make the heart\u2019s work easier by lowering blood pressure, for example. <\/p>\n
As scientists figure out how dilated cardiomyopathy develops, they may also be able to figure out how to keep the heart muscle from changing shape in the first place. Those days are far off, but this research is a step in the right direction, Seidman says. \u201cIt allows us to focus on what we don\u2019t know yet,\u201d she says. Discovering the role of mutations in titin is like finding one important piece of a jigsaw puzzle. \u201cThere are still a lot more pieces in the box that we need to sort through, but that\u2019s a big deal.\u201d <\/p>\n<\/p>\n
Continued here: Dilated cardiomyopathy, a common cause of heart failure, can be attributed to defects in any of more than 40 different genes. Continue reading
\nResearchers Identify New Gene Mutations that Cause Heart Disorder<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"