Mount Sinai Scientists Identify First Gene Linked to Heart Muscle Disease in Children
Findings show several FDA-approved drugs may also be effective in patients diagnosed with dilated cardiomyopathy.
Scientists at Icahn School of Medicine at Mount Sinai, along with collaborators at institutions in India, Italy, and Japan, have identified the first gene linked to childhood-onset familial dilated cardiomyopathy (DCM), one of the most common heart muscle diseases in children. It is a progressive and potentially fatal heart condition resulting from an enlarged and weakened heart muscle.
The study, published in Nature Genetics, also revealed a link between DCM and excessive activation of the protein, mTOR. Currently, there are several existing FDA-approved blocking drugs for this protein including rapamycin, currently used primarily as an immunosuppressant after solid organ transplantation. Promising preliminary research indicate that at least one of these mTor inhibitors may be effective in halting progression of the disease.
"One day we hope to have therapeutic treatments for all of the different genetic variations that contribute to this complex disease, not just medications that delay heart failure," said Valentin Fuster, MD, PhD, Director of Mount Sinai Heart, the Zena and Michael A. Wiener Cardiovascular Institute, and the Marie-Josée and Henry R. Kravis Center for Cardiovascular Health, and Physician-in-Chief at The Mount Sinai Hospital. "This extraordinary study may lead to the first of those treatments and offers new hope to a group of patients with no other medical recourse."
DCM is a disease characterized by progressive weakening and enlargement of the heart muscle, which can lead to heart failure and premature death. Experts estimate that it likely affects about one in every 250 individuals. The genetically complex disease is associated with variants in at least 40 genes, with the underlying causes of 50-60 percent of cases remaining unknown. Currently, DCM has no cure as the available medicines only delay the onset of congestive heart failure or the need for aggressive therapies like heart transplantation.
In this research effort, scientists conducted DNA sequencing on more than 500 adults and children with DCM and more than 1,100 healthy controls from several ethnically distinct cohorts to learn about the genetic profile of the disease. They identified changes in the RAF1 gene as a cause of DCM and found that patients with these mutations were more likely to have been diagnosed with the disease as children. These genetic variants accounted for approximately 10 percent of childhood-onset DCM cases in the populations studied. Also, the RAF1 variants increased activity of the protein mTOR, which can be inhibited with several drugs already approved by the FDA.
To validate their findings, the scientists modeled these genetic changes in zebrafish. When treated with the medication, rapamycin, one of the FDA-approved drugs used to inhibit the mTOR protein, the zebrafish heart defects were partially reversed and protein levels shifted to a healthy profile.
"There are currently virtually no treatments for dilated cardiomyopathy targeted to genetic changes, so the finding that commercially available drugs may be effective for patients with childhood-onset, RAF1-induced DCM is a remarkable advance," said Bruce Gelb, MD, Director and Gogel Family Professor of the Mindich Child Health and Development Institute at Mount Sinai and senior author. "The critical next step is to study this biological mechanism in a mammalian model and generate data to support a clinical trial of rapamycin or a related drug for DCM patients who have these genetic variants."
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Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children's Hospital among the country’s best in 4 out of 10 pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.