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Press release
Discovery of the first gene involved in a very common cardiac arrhythmia | |||
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Paris, January 9, 2003 |
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from the "Laboratoire Génétique des Canaux Ioniques"
(Ionic Channel Genetics Laboratory) of the Institut de Pharmacologie Moléculaire
et Cellulaire – CNRS – Université de Nice, Sophia-Antipolis,
in collaboration with geneticists from Shanghai, have discovered the first
gene responsible for atrial fibrillation, a very common form of cardiac
arrhythmia. This gene, KCNQ1 (on chromosome 11), encodes one of the two
subunits of a potassium channel present in heart tissue. Potassium channels
are involved in other heart conditions known at this time. This research
was published in Science of January 10, 2003. Atrial fibrillation affects approximately 1% of young adults and 5% of people over 65 years old. Although not lethal, it is nevertheless disabling, leading to fatigue, shortness of breath, palpitations and a variety of cardio-vascular disorders. As a result, it accounts for a large portion of health expenditures. The discovery of the genetic origin and the exact physiological mechanism of this disorder began in the province of Shandong, in China. Geneticists from Shanghai found the S140G mutation of the KCNQ1 gene in a Chinese family in which many of the members suffered from atrial fibrillation. They contacted the Ionic Channel Genetics Laboratory, known for its research on this gene. The French researchers, under the supervision of Jacques Barhanin, Research Director at the CNRS, were then studying the physiological mechanisms of this mutation which causes atrial fibrillation. Resting heart cells maintain a membrane potential of approximately -80 mV (millivolts). Electrical activity can be seen by the changes in this membrane potential. It is the action potential whose frequency and duration regulate heartbeat and which can be measured by an electrocardiogram. This electrical activity is due to the extremely precise functioning of a group of ionic channels. Among them, the potassium channels play an essential role in regulating the duration of the action potential that must be perfectly adapted to heart rate which is, itself, related to our physical activity. The disruption of the activity of only one of these channels may lead to different types of arrhythmia, some which may result in sudden death. The S140G mutation found in the Chinese family is located on the gene of one of these potassium channels and is known as the KCNQ1 gene. Researchers at Sophia-Antipolis showed that this mutation leads to an abnormal increase of the channel's activity. This gain of function has two physiological consequences. The duration of the action potential and that of the refractory period between two action potentials (during which contractions are impossible) are shortened. Action potentials then occur before they are supposed to, leading to spastic and uncoordinated contractions, causing the atrium to begin fibrillating. Mutations that induce a loss of function of this channel are already known to be the cause of another type of arrhythmia, ventricular tachycardia, which is much more serious since it often leads to sudden death. Therefore, distinct mutations in the same canal may cause two types of arrhythmia whose underlying mechanisms make them appear to be completely different from each other. Genetic forms are very rare among the many cases of atrial fibrillation. Nevertheless, other types of cardiac arrhythmia studied in the past have shown that the channel with the genetic disease mutation is also often involved in epigenetic arrhythmia. In the latter case, the channel is often affected by the side effects of a drug. Therefore, knowledge of the genetic mutations of these channels make it possible to precisely determine the mechanisms underlying arrhythmia, leading to the development of more effective treatments in the future. Faced with stiff competition in the field of heart disease research, particularly from the United States, this discovery, the fruit of a collaboration between a French group and a Chinese team is a true accomplishment. France thus affirms its position in this very important field, along with another French research team under the supervision of Professor Denis Escande (INSERM U533, Nantes) who have just found a second gene involved in atrial fibrillation. This French success was due to the joint efforts of different teams including those of Jacques Barhanin (Sophia-Antipolis), Denis Escande, Hervé Le Marec (Nantes), Pascale Guicheney (Institut de Myologie, La Pitié-Salpêtrière), as well as the team of Professor Philippe Coumel at Hôpital Lariboisière. Researcher
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