Feb. 7, 2003 BALTIMORE, Md. -- Fatal, electrical chaos can develop in the hearts of otherwise healthy people who produce a defective accessory protein called ankyrin-B, reports W. Jonathan Lederer of the University of Maryland Biotechnology Institute (UMBI) and collaborators, in the February 6 issue of the scientific journal Nature.
By discovering the molecular and cellular causes of the electrical chaos-known as Long QT Syndrome Type 4, or LQT4-Lederer and collaborators open the door to possible therapies and diagnostics for this and related heart diseases. The work also provides a clue to how important, specific proteins are organized within heart cells.
Several years ago, clinical researchers in France, headed by Denis Escande, discovered an inheritance pattern in members of a family who had been dying suddenly and unexpectedly in the prime of life. Lederer's team at UMBI and the University of Maryland at Baltimore and researchers at Duke University, headed by Vann Bennett, collaborated with the French by applying state-of-the-art heart physiology tools to mouse heart cells in order to find the cause of the sudden deaths.
Cardiovascular disease, including cardiac arrhythmia and sudden cardiac death and stroke are the leading causes of death worldwide. The term QT in LQT4 and other long QT syndromes refers to a time period, normally about 300 milliseconds (read between points Q and T on an electrocardiogram) when each electrical pulse, or action potential, starts a heart beat. Longer QT periods can signal heart problems.
The researchers discovered that the LQT4 is linked to a genetic defect in humans and in a mutant mouse developed by the Bennett laboratory. The defect is expressed as an inadequate amount of an important adaptor protein called ankyrin-B that is involved in enriching cells with key proteins at specific locations within the cell. Lederer's group studied the dynamic physiology of single cells in the Bennett mouse.
The reduction or absence of functional ankyrin-B in the cells causes proteins involved in cellular calcium regulation to be inadequate or absent from critical locations within the cell. Cells load up with too much calcium. The change in calcium causes the heart to beat improperly and, in the case of LQT4, chaotically. The electrical chaos that can cause death appears to be triggered by unexpected stress and possibly an increase in adrenaline - as would happen when individuals are startled, says Lederer. Even then, the death-causing electrical chaos is rare.
Humans and animals are afflicted with LQT4 when only one of the two genes for ankyrin-B is defective or absent. When both are absent, the condition is lethal.
However, says Lederer, many individuals survive for a long time with the defect. The rare occurrence of the development of calcium-dependent electrical chaos in the heart means that most individuals have normal heart behavior even when they are afflicted with LQT4.
Finding the defective protein to be ankyrin-B was somewhat of a surprise, says Lederer, a world leader in studies ion channels and calcium sparks in heart cells. "We thought it would make sense if the defective protein were a channel protein. The other long QT syndromes are caused by defects in channel proteins. This is the first example of a cytoskeletal or structural protein causing such an arrhythmia."
Lederer and his team collaborated with other primary investigators from Duke University and the Howard Hughes Institute headed by Vann Bennett and Peter Mohler and with investigators at the French Institute of Health and Medical Research (INSERM) in Nantes, France, headed by Denis Escande. Key local investigators on the Lederer team included S. Guatimosim, L-S. Song and K. Dilly from MBC and T. B. Rogers and W. duBell from the School of Medicine at University of Maryland, Baltimore.
The University of Maryland Biotechnology Institute was mandated by the state of Maryland legislature in 1985 as "a new paradigm of state economic development in biotech-related sciences." With five major research and education centers across Maryland, UMBI is dedicated to advancing the frontiers of biotechnology. The centers are the Center for Advanced Research in Biotechnology in Rockville; Center for Biosystems Research in College Park; and Center of Marine Biotechnology, Medical Biotechnology Center, and the Institute of Human Virology, all in Baltimore.
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