When Marion Greaser set out to study titin, the largest natural protein known to man, his goal was to answer some basic questions about its role in the body. A major protein of skeletal muscle that’s also found in heart tissue, titin gives muscle its elasticity and is known for its massive size, which ranges from around 27,000 to 33,000 amino acid residues in length.
“Initially we were just going to look at whether titin was related to muscle growth in animals,” says Greaser, a CALS professor of animal sciences.
Working in rats, his team looked at changes in the size of the titin protein over the course of animal development—and immediately came across something strange. In most cases the titin protein shifted from a larger form to a smaller form during development due to natural changes in protein processing known as alternative splicing. But in some rats the titin didn’t change. It stayed big.
The team wondered if they’d mixed up the samples. “But we’d kept good track of things and, in fact, all of the weird samples were from the same litter of rats,” says Greaser. “Then the light bulb went off: There must be some genetic reason why these samples are different. These rats had a genetic mutation affecting the alternative splicing of the titin.”
But where was the mutation? They first checked the titin gene itself, but it was fine. With hard work, they were able to pinpoint the mutation to a little-studied gene called RBM20, which had been previously linked to dilated cardiomyopathy and sudden death in humans.
Dilated cardiomyopathy affects approximately one in 2,500 people. Sufferers have enlarged hearts, with thin walls, that don’t pump blood very well. People with the RBM20 mutation need heart transplants and, without them, tend to die quite early: between ages 25 and 30.
Scientists first linked RBM20 to hereditary dilated cardiomyopathy in 2009, but they hadn’t yet figured out how a faulty RBM20 gene worked—or didn’t work—to cause disease inside the body.
Greaser’s accidental discovery, as described in Nature Medicine, filled in the blank. In healthy individuals, the RBM20 protein is involved in the alternative splicing that helps trim titin down to its smaller, adult form. Without it, titin doesn’t get processed correctly, and the presence of extra-large titin in heart tissue leads to disease.
“Now doctors can analyze people showing symptoms of dilated cardiomyopathy, see if they’re carrying this mutation and factor this information into their treatments,” says Greaser. That treatment would probably start with careful monitoring to catch any further deterioration of the heart condition, Greaser notes.