TTN

The TTN gene provides instructions for making titin, the largest known protein. This protein plays an important role in muscles the body uses for movement (skeletal muscles) and in heart (cardiac) muscle. Slightly different versions (isoforms) of titin are made in different muscles.

Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic unit of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of the protein's main jobs is to provide structure, flexibility, and stability to these cell structures. Titin interacts with other muscle proteins, including actin and myosin, to keep the components of sarcomeres in place. Titin also contains a spring-like region that allows muscles to stretch. Additionally, researchers have found that titin plays a role in chemical signaling and in assembling new sarcomeres.

tibial muscular dystrophy - caused by mutations in the TTN gene

Several mutations in the TTN gene have been identified in people with tibial muscular dystrophy. A particular mutation has been found to cause the disorder in all affected people of Finnish descent. This genetic change deletes several protein building blocks (amino acids) and replaces them with other amino acids near the end of the titin protein. This complex mutation is known as FINmaj. TTN mutations also cause tibial muscular dystrophy of varying severity in non-Finnish European populations.

Researchers predict that the TTN mutations responsible for tibial muscular dystrophy, including FINmaj, disrupt titin's interactions with other proteins within sarcomeres. Mutations may also interfere with the protein's role in chemical signaling. The altered titin protein disrupts normal muscle contraction, which causes muscles to weaken and waste away over time. It is unclear why these effects are usually limited to muscles in the lower legs.

other disorders - caused by mutations in the TTN gene

Mutations in other regions of the TTN gene cause several disorders of cardiac and skeletal muscle. Two of these disorders, familial hypertrophic cardiomyopathy type 9 and dilated cardiomyopathy type 1G, primarily affect cardiac muscle. Hypertrophic cardiomyopathy is a thickening of the cardiac muscle that forces the heart to work harder to pump blood. This condition is often associated with an abnormal heartbeat (arrhythmia) and can lead to heart failure and sudden death. Dilated cardiomyopathy is a condition that weakens and enlarges the heart, preventing it from pumping blood efficiently. Dilated cardiomyopathy also increases the risk of heart failure and premature death. Researchers have found at least two TTN mutations in people with familial hypertrophic cardiomyopathy type 9 and about six mutations in people with dilated cardiomyopathy type 1G.

TTN mutations are responsible for two additional skeletal muscle disorders: limb-girdle muscular dystrophy type 2J (LGMD2J) and hereditary myopathy with early respiratory failure. Limb-girdle muscular dystrophy is a group of related disorders characterized by muscle weakness and wasting, particularly in the shoulders, hips, and limbs. Like some cases of tibial muscular dystrophy, LGMD2J results from the FINmaj mutation in the TTN gene. When this mutation is present in one copy of the gene in each cell, it causes tibial muscular dystrophy; when it is present in both copies of the gene, it causes the much more severe LGMD2J. A different TTN mutation has been found to cause hereditary myopathy with early respiratory failure. This rare form of muscular dystrophy affects both skeletal muscles and muscles needed for breathing, such as the diaphragm.

The TTN mutations responsible for these disorders of cardiac and skeletal muscle likely disrupt the normal structure and function of titin. The genetic changes may alter titin's interactions with other muscle proteins or disrupt its role in chemical signaling. Researchers are working to determine why some conditions resulting from TTN mutations predominantly affect cardiac muscle and others predominantly affect skeletal muscle. They suspect that these differences may be related to the location of mutations in the TTN gene and the many varieties of titin that are produced in different muscles.