Mutations in gigantic gene responsible for common heart muscle disease

BOSTON, MA—Mutations in TTN—the largest gene in the human genome—cause idiopathic (unknown cause) dilated cardiomyopathy (DCM), a common form of heart failure, according to a study by Brigham and Women's Hospital (BWH) researchers. The TTN gene encodes a protein that functions as a scaffold for assembly of contractile proteins in muscle cells and also regulates the production of force in cardiac muscle cells.

Because of its enormous size, the TTN gene was, until recently, too difficult to sequence and analyze in large numbers of patients. But with the development of next-generation sequencing technologies, the time was ripe to tackle TTN. Christine Seidman, MD, BWH Cardiovascular Genetics Center director and a team of dedicated scientists at Harvard Medical School; Imperial College, London; University of Colorado; and physicians at BWH took on the challenge to comb through the gigantic gene. Their study unveils how mutated TTN genes can lead to structural deformations in heart muscle fibers, which may then lead to heart muscle disease. The study will be published in the February 16, 2012 issue of The New England Journal of Medicine.

Researchers analyzed genetic samples from 312 people diagnosed with DCM, 231 with another heart muscle disease called hypertrophic cardiomyopathy (HCM), and 249 people without heart disease. They identified 72 mutations in the TTN gene that foreshorten the encoded protein. These shortened titin proteins lack regions involved in regulating force production in heart cells. Many more mutations were found in those with DCM compared to healthy individuals and those with HCM, indicating that TTN gene mutation causes DCM, but rarely causes HCM.

Moreover, the study notes that outcomes of patients with DCM were similar regardless of whether or not a person has a TTN gene mutation. However, among those that did have TTN mutations, adverse events such as cardiac transplantation, implantation of a ventricular assist device, or death occurred earlier in men than women. Seidman believes that the study findings will help improve future diagnosis and treatment of heart diseases.

"Early diagnosis of any disease, including DCM, can allow interventions that may prevent some of the devastating outcomes, such as sudden cardiac death from an arrhythmia or development of heart failure," said Seidman. "By knowing that TTN mutations account for a substantial amount of idiopathic DCM, we now will have the opportunity for early diagnosis in lots of at-risk individuals, and any person who has a family member with idiopathic DCM."

This research was supported by funding from Howard Hughes Medical Institute; National Institutes of Health Leducq Foundation; American Heart Association and Muscular Dystrophy Association; UK National Institute for Health Research Cardiovascular Biomedical Research Unit (Royal Brompton and Harefield NHS Foundation Trust & Imperial College), The British Heart Foundation and the MRC UK; and J. Ira and Nicki Harris Family Research Award.

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare, an integrated health care delivery network. BWH is the home of the Carl J. and Ruth Shapiro Cardiovascular Center, the most advanced center of its kind. BWH is committed to excellence in patient care with expertise in virtually every specialty of medicine and surgery. The BWH medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in quality improvement and patient safety initiatives and its dedication to educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Biomedical Research Institute (BRI), www.brighamandwomens.org/research, BWH is an international leader in basic, clinical and translational research on human diseases, involving more than 900 physician-investigators and renowned biomedical scientists and faculty supported by more than $537 M in funding. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative. For more information about BWH, please visit www.brighamandwomens.org.