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Mutation in gene critical for human development causes lethal arrhythmia

December 28, 2011 - Washington

Altered function of a gene that is critical for human development interferes with the growth of the cardiac conduction system (CCS) and causes lethal arrhythmias, a new study has claimed.

Arrhythmia is a potentially life-threatening problem with the rate or rhythm of the heartbeat, causing it to go too fast, too slow or to beat irregularly.

The CCS regulates the rate and rhythm of the heart. It is a group of specialized cells in the walls of the heart. These cells control the heart rate by sending electrical signals from the sinoatrial node in the heart's right atrium - upper chamber, to the ventricles - lower chambers, causing them to contract and pump blood.

The biologic and genetic mechanisms controlling the formation and function of the CCS are not well understood, but new research with mice shows that mutation of Tbx3 gene interferes with the development of the CCS and causes arrhythmias.

Researchers led by the University of Utah have shown that the CCS is extremely sensitive to levels of Tbx3. Mouse embryos with Tbx3 levels below a critical threshold suffered arrhythmia and couldn't survive. As the levels of Tbx3 were increased, mice survived to birth, but as adults they developed arrhythmias or had sudden death.

Anne M. Moon, corresponding author of the study, said that Tbx3 dysfunction merits further investigation as a cause of acquired and spontaneous arrhythmias.

"The cardiac conduction system is very sensitive to Tbx3," Moon said.

"Tbx3 is required for the conduction system to develop, mature, and then continue to function properly," she added.

The Tbx3 Protein, which is a transcription factor encoded by the TBX3 gene, has been linked to heart development, but its role is not yet clearly defined. Moon and her colleagues, including first author Deborah U. Frank, found that slight alterations in the structure of the Tbx3 gene alter the level of the protein in mice.

When this happens, it can impair the electrical signal in the sinoatrial node and block the atrioventricular node, which conducts electrical signals from the atria to the ventricles. The result is lethal arrhythmias in embryonic and adult mice.

The study has been published in Proceedings of the National Academy of Sciences early edition.


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