Scientists have identified a genetic mutation causing the irregular heartbeats that characterize atrial fibrillation (AF). Nearly one out of every 20 individuals over age 65 suffer from this cardiac arrhythmia, which is increasing in prevalence as the population ages. When left unchecked, AF can lead to heart muscle dysfunction, embolism, ventricular arrhythmia, and heart failure. Studying families with a rare inherited form of AF, a collaborative research team composed of scientists in China and France has identified the disease-causing gene as KCNQ1, which encodes a protein subunit of an ion channel controlling the movement of charged potassium through a cell membrane. The discovery is reported in the 10 January 2003 issue of Science.
This new understanding of the molecular basis of atrial fibrillation may lead to better pre-symptomatic diagnosis of the disorder and to the development of new therapies, according to corresponding authors, Yi-Han Chen of Tongji University, Shanghai, China and Shi-Jie Xu of Chinese National Human Genome Center, Shanghai, China.
The scientists studied a four-generation family in China with a history of AF. Of the 44 living members of this family from both rural villages and nearby cities in northern Shandong Province, sixteen have cases of AF, all of which the researchers confirmed were hereditary. Gene mapping studies led the researchers to the critical region of chromosome 11 that was linked to AF. Sequence analysis revealed that there was a specific nucleotide substitution in the KCNQ1 gene in all of the family members affected with AF, but not in unaffected family members. Cell culture analyses confirmed that this genetic alteration disrupted the function of the KCNQ1 potassium channel.
The KCNQ1 potassium channel, like other ion channels, controls the electrical activity of the heart in excitable heart cells, or myocytes. That is, the inflow or outflow of ions through a cell membrane impacts how a heart beats--steadily and predictably in a healthy individual, or occasionally rapidly and unpredictably in AF patients. "The mutation in KCNQ1 causes a marked enhancement of its function, tips the normal balance of the process, and renders the cardiac myocytes more susceptible to atrial fibrillation," Chen and Xu said.
The KCNQ1 potassium ion channel was a suspect in the case of familial atrial fibrillation, because it had already been linked to other heart conditions, such as familial ventricular fibrillation and long QT syndrome. The mutation in KCNQ1 that leads to AF keeps the potassium channel open, while a KCNQ1 mutation for long QT syndrome does the opposite. Cardiac ion channels have diverse functional behaviors, which can lead to different types of cardiac disorders, Chen and Xu explained.
Several small hereditary AF families and some individuals with isolated cases OF AF did not have KCNQ1 mutations, according to the authors. This suggests that additional genes are likely to be involved in the pathogenesis of the disorder.
Currently, AF therapy includes pharmacologic and nonpharmacologic treatments. Some of the pharmacologic treatments have been used for decades and can occasionally have serious side effects. Nonpharmacologic treatments, which include defibrillators, atrial pacing methods and surgery, can be complex, hard to conduct, or damage-causing. "Our results may suggest new therapeutic strategies for both the inherited and the more commonly acquired forms of AF," said Chen and Xu.
The Science research took about three years to complete. "At last a coherent story was achieved -- from clinical symptom, to mutation identification, to revelation of channel malfunction -- and ultimately the work has provided new insight into the mechanism of atrial fibrillation," the researchers noted.
Although this research was conducted in China, the prevalence of atrial fibrillation is generally higher in western societies. It is not clear, however, whether the difference is due to genetic or environmental factors, according to cited literature. The researchers next plan to study how the AF-causing KCNQ1 mutation influences heart rhythm, and why some carriers of the mutation are more or less susceptible to developing full-blown AF.
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Shi-Jie Xu is also with Institute for Biological Science-Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai, China. Co-authors on this study are Wen-Yuan Xu, Xiao-Yan Su, Yi-Qing Yang, Yi Liu, Hong-Ju Xu, Xiao-Fei Li, Ning Ma and Chun-Ping Mou at Tongji U.-Tongji Hospital in Shanghai, China Saiïd Bendahhou and Jacques Barhanin at CNRS in Sophia Antipolis, France; Xiao-Liang Wang and Hong-Wei Jin at Chinese Academy of Medical Sciences in Beijing, China; Ying Wang, Hao Sun, Qi-Nan Zhuang, Yue-Bin Li, Zhu Chen, and Wei Huang at Chinese National Human Genome Center in Shanghai, P.R. China; Zhu Chen and Wei Huang are also at Rui Jin Hospital-Shanghai Second Medical University in Shanghai, P.R. China. Wei Huang is also at Chinese Academy of Sciences in Shanghai, P.R. China.
This study was conducted with support from the National Natural Science Foundation, Chinese High Tech Program, the National Key Program on Basic Research, Foundation for University Key Teacher by the Ministry of Education, the Shanghai Science and Technology Development Fund, Shanghai Commission for Education, Centre National de la Recherche Scientifique, and Fondation pour la Recherche Médicale and the Association Française contre les Mypopathies (S.B.)
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