Every year, sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being sought, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. Most congenital LQT syndrome patients have mutations in either the KCNQ1 or KCNH2 (human ether a-go-go- related) genes, which encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that KCNQ1 (LQT1) mutations and KCNH2 (LQT2) mutations typically result in a loss of function. Many LQT1 and most LQT2 mutations cause Kv7.1 and Kv11.1 to be retained in Endoplasmic Reticulum (ER), thereby decreasing the number of functional channels expressed at the cell surface. Thus far, mechanisms that increase the ER export and functional expression have only been identified for trafficking deficient LQT2 mutations, and, unfortunately, most of these mechanisms do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study cellular properties that direct the ER retention for LQT1 and LQT2 mutations, and the ER export and trafficking for wild type (WT) Kv7.1 and Kv11.1. We will test that hypothesis: The ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that modulating interactions between chaperones, co-chaperones, and Kv7.1 or Kv11.1 will selectively increase the functional expression for different trafficking deficient LQT1 and LQT2 mutations, and that the vesicular transport properties for Kv7.1 and Kv11.1 can be manipulated to increase their functional expression.
Every year sudden cardiac death claims up to 25,000 people that do not have structural heart disease. Genetic and acquired causes for these cases of sudden cardiac death are increasingly being identified, and hundreds of mutations have been linked to the pro-arrhythmia disease Long QT (LQT) syndrome. About one in 7,000 people have LQT1 or LQT2, which is caused by mutations in either the KCNQ1 or KCNH2 genes, respectively. These genes encode the voltage-gated K+ channel 1-subunits Kv7.1 and Kv11.1 that underlie the delayed rectifier K+ current in the heart. Studies suggest that LQT1 and LQT2 mutations typically result in a loss of function. The mechanisms that underlie the loss of function varies, but it is now recognized that many of these mutations decrease the number of functional channels expressed at the cell surface, because they are retained inside the cell in the Endoplasmic Reticulum (ER). Thus far, mechanisms that increase the functional expression for these mutations have only been identified for LQT2 and do not have therapeutic potential. In order to rationally develop therapeutic strategies for treating patients with trafficking deficient LQT1 or LQT2 mutations, we propose to study the cellular quality control and vesicular transport properties for Kv7.1 and Kv11.1. We will test the hypothesis that the ER retention of LQT1 and LQT2 mutations is regulated by different components of cellular quality control, and Kv7.1 and Kv11.1 traffic in distinct vesicular transport pathways. We anticipate that we will identify novel ways to increase the functional expression for trafficking deficient LQT1 and LQT2 mutations.
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