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A genetic defect may make some people with otherwise structurally normal hearts more susceptible to exercise-induced cardiac arrhythmias, according to a team of P&S researchers. Their findings, which were reported in the June 27 issue of Cell, show that a deficiency of FKBP12.6, a protein that binds to the intracellular cardiac calcium channel (ryanodine receptor, or RyR2) may result in abnormal calcium release and be linked to exercise-induced cardiac death. The researchers also identified the biophysical properties of three distinct RyR2 mutations linked to these ventricular arrhythmias.

Headed by Dr. Andrew Marks, chairman of physiology and cellular biophysics and director of the Center for Molecular Cardiology, the team investigated the function of FKBP12.6, its effects on calcium channel function, and its association with exercise-induced ventricular arrhythmias (sudden cardiac death). Their focus was on a possible connection between a deficiency of FKBP12.6 and irregular calcium channel function. In normal cardiac muscle, the RyR2 releases the calcium required for muscle contraction. FKBP12.6 stabilizes the RyR2, preventing a release of too much calcium, which can trigger erratic heart activity during the resting phase of the cardiac cycle.

Dr. Marks' team studied genetically modified mice deficient in the FKBP12.6 gene to observe heart function at rest and during exercise. "The research showed that the FKBP12.6-deficient mice consistently exhibited exercise-induced ventricular arrhythmias that cause sudden cardiac death – suggesting that ‘leaky' RyR2 channels can trigger fatal cardiac arrhythmias," says Dr. Xander H.T. Wehrens, a P&S postdoctoral scientist and first author of the report in Cell.

Dr. Marks says these findings will significantly advance discovery of possible treatment. "Our findings show that if we can develop therapies that influence the binding of FKBP12.6 in the calcium channel, we can prevent one of the most common and baffling causes of cardiac death – exercise-induced arrhythmias in individuals with otherwise healthy hearts. Moreover, our findings may also provide clues for novel strategies to prevent cardiac arrhythmias in millions of patients with heart failure who have a similar leak in their calcium channels."

Funding for this work was provided by the National Heart Lung and Blood Initiative.


Columbia researchers have found a gene in mice that may act as a tumor suppressor. The finding may provide new insights into preventing cancer, but it is not known whether the gene also suppresses tumors in humans.

The researchers – led by Dr. I. Bernard Weinstein, Frode Jensen Professor of Medicine and professor of genetics & development at P&S and professor of environmental health sciences at the Mailman School of Public Health – found that the loss of this gene, HINT1/PKCI, makes mice more susceptible to developing stomach cancer. They gave a chemical carcinogen to normal mice and to mutant mice that lacked the gene that encodes for HINT1/PKCI. Both types of mice developed cancer of the stomach lining but the mutant mice had more tumors that were also larger and more malignant than those of the normal mice.

Next, they made cell cultures of embryonic tissue from both kinds of mice. In the normal mice, the cells died after a few generations, as expected. But the cells from the mutant mice grew and divided rapidly – a sign that the cells might be in the early stages of becoming cancer cells. The cells from the mutant mice also were more resistant to the killing effects of X-ray radiation. These findings suggest that the HINT1/PKCI gene confers resistance to cancer and may normally function as a tumor suppressor gene like the p53 gene.

The researchers now are investigating the gene's role in breast cancer in mice and in the future they will study its possible role in human cancer. "If the HINT1/PKCI gene is important in inhibiting human cancer, it might be possible to either replace the gene or mimic its function as a new approach to prevention and treatment," Dr. Weinstein says.

The study's findings were published in the June 24 issue of the Proceedings of the National Academy of Sciences.

The research was supported by the National Cancer Institute, the National Foundation for Cancer Research and the T.J. Martell Foundation.

— Matthew Dougherty

Witnessing parental violence and having a history of adolescent behavioral problems are the two greatest risk factors for children becoming abusive in their adult romantic relationships, according to a new study by researchers at P&S and the New York State Psychiatric Institute.

The researchers looked at several potential risk factors in a community sample of 543 children who were followed for 20 years into adulthood. A third risk factor, coercive parenting, also increased the risk of perpetrating domestic violence. The risk factors apply to both males and females; girls were just as likely to abuse their partners as boys.

The findings suggest that efforts to prevent domestic violence need to focus on young children rather than adolescents. "Targeting children who have been exposed to parents' aggression, and also boys and girls who display problems with aggression, when they are young is going to be the best way to stop domestic violence from destroying families," says the study's lead author, Dr. Miriam Ehrensaft, assistant professor of clinical psychiatry.

This research was funded by the National Institute of Justice and the National Institute of Mental Health.

— Susan Conova


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