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A team of researchers at Weill Cornell Medical College, led by Dr. Craig T. Basson, has discovered a genetic mutation that causes cardiac myxomas (or Carney complex), the most common tumor of the heart in adults. The mutation causes an insufficiency in a common enzyme that regulates molecular signaling for growth and metabolism within cells throughout the body as well as the heart. The discovery may lead not only to a new genetic technique for early diagnosis of the tumor, and thereby improved treatment, but ultimately to novel therapies to regenerate heart cells/tissue in individuals with heart failure and weakened hearts.

The study, which is available electronically today online and will be published in the September 1 issue of the Journal of Clinical Investigation (JCI), demonstrates that mutations in the PRKAR1alpha [protein kinase A R1 alpha] gene that encodes the R1alpha regulatory subunit of the well-known cAMP-dependent protein kinase A enzyme cause Carney complex and cardiac myxomas.

Cardiac myxomas most commonly affect middle-age women (but can affect individuals of any age or gender) and frequently cause symptoms through severe heart failure and debilitating stroke. Seven percent of these tumors are the result of an inherited disorder in families, most recently referred to as Carney complex. The affected individuals may also have excessive "freckling" of the skin, other tumors, and various hormonal abnormalities.

Through the study of three unrelated families, the researchers showed that the gene defect which causes Carney complex was located within a 12 million basepair region on the long arm of chromosome 17. Using their own refined maps of this region as well as maps and sequences developed through the Human Genome Project, the investigators then demonstrated that the PRKAR1alpha gene was located with the same interval that included the Carney complex gene defect. Dr. Basson's laboratory then performed mutational analysis of DNA samples from individuals in Carney complex families by sequencing the PRKAR1alpha gene in each individual, and found that individuals with cardiac myxomas and Carney complex had small deletions within the gene of 1 or 2 basepairs. These deletions result in abnormal PRKAR1alpha message RNA in the cell that is degraded by cells. Thus, affected individuals have a 50% reduction in the amount of R1 alpha regulatory subunit. Tumor formation in the heart as well as other organs appears to result both from loss of the subunit as well as consequent increases in other subunits as the cell inappropriately tries to compensate for the gene defect.

The findings have significant clinical applications. Through genetic analysis, physicians will now be able to identify certain individuals at risk for developing these heart tumors. These persons could be followed closely—say, annually—with noninvasive echocardiograms to identify tumors that need to be removed before they cause heart failure, stroke, and ultimately, death.

Moreover, because cells in cardiac myxomas have the potential to spontaneously develop into cell types found throughout the body (including muscle cells), it is thought that they arise from very rare primitive "stem" cells in the heart. In the future, it may be possible, through manipulation of the protein kinase A enzyme in these heart cells, to regenerate dead or weakened heart muscle in individuals who have suffered heart attacks or severe cardiac ischemia.

Dr. Craig T. Basson, who is an Assistant Professor of Medicine in the Division of Cardiology at Weill Cornell Medical College and directs the Molecular Cardiology Laboratory, has long focused on the identification of such cardiac precursor cells that could be induced to become new cardiac muscle. Dr. Basson, in fact, turned his attention to the disease of cardiac myxoma in order to search for these precursor cells. This search—and his investigation of particular families with Carney complex—led to his discovery of the gene responsible for inducing otherwise quiescent cells within the heart to proliferate. With understanding of this mechanism in hand, Dr. Basson and others may one day use such heart cells to help repopulate infarcted or damaged myocardium.

Joining Dr. Basson in this research were Weill Cornell co-authors Drs. Mairead Casey, Carl Vaughan, Jie He, Cathy Hatcher, and Jordan Winter; Drs. Stanislawa Weremowicz and Cynthia Morton of Harvard Medical School; and Drs. Kate Montgomery and Raju Kucherlapati of Albert Einstein College of Medicine.

The research was generously supported by an American Cardiology/Merck Research Fellowship; a National Heart, Lung, and Blood Institute (NHLBI) Minority Postdoctoral Fellowship; an American Heart Association Student Scholarship in Cardiovascular Disease and Stroke; a National Cancer Institute (NCI) grant; and grants from the Wendy Will Case Cancer Fund, the American Heart Association, NYC Affiliate, Inc., and the NIH/NHLBI.