New insight into common heart rhythm disorder
Fondation Leducq-supported researchers in Iowa and France have identified a gene variant that causes a common heart rhythm disorder called “sinus node dysfunction.” The report, published in the October 7th issue of Proceedings of the National Academy of Sciences, includes among its authors Dr. Jean-Jacques Schott of the Preventing Sudden Cardiac Death network and Drs. Mark E. Anderson and Peter J. Mohler of the Alliance for Calmodulin Kinase II Signaling in Heart Disease network. The research was also supported by the National Institutes of Health, the American Heart Association, the Pew Scholars Trust, and the Assocation Francaise contre les Myopathies.
Normally, cardiac rhythm is maintained by a small group of cells in the sinoatrial node, often called “pacemaker” cells. The cells are characterized by automaticity: they spontaneously undergo electrical depolarization due to the movement of ions across the cell membrane. Dysfunction of these cells, or sinus node dysfunction (SND), can lead to dangerously low heart rates, which may be fatal. In fact, SND is the reason for more than half of all pacemaker implantations, at an annual cost of nearly $2 billion in the US. The molecular mechanisms underlying SND were unknown, but the presence of SND in patients who otherwise had no cardiac abnormalities suggested that at least some cases of SND could have a genetic basis.
Ankyrins are adaptor proteins that link proteins in the cell membrane to proteins inside the cell. This linkage is important for the proper location and function of membrane proteins like ion channels, which control the passage of ions into and out of the cell. Variants in the ANK2 gene, which codes for the ankyrin-B (AnkB) protein, had been previously implicated in other heart rhythm disorders.
The researchers sequenced the ANK2 gene in members of 2 large French families with SND. In affected members of the first family, they found a mutation that caused the loss of AnkB function. In affected members of the second family, they found reduced AnkB levels in heart tissue. Supporting the hypothesis that abnormal AnkB was implicated in SND, mice with only 1 copy of the ANK2 gene were found to have much lower heart rates compared to normal mice with 2 copies. Moreover, sinoatrial cells with only 1 copy of the ANK2 gene had abnormalities in the levels and location of other important proteins. These cells also exhibited abnormal calcium ion flux and loss of automaticity. These results highlight the importance of AnkB and membrane protein organization for the proper functioning of sinoatrial cells and identify one pathway in the development of SND.
Click on the title to access the article in PNAS: Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease