| The long QT syndrome (LQTS) is a rare genetic disorder resulting in sudden cardiac death in otherwise young and healthy individuals. Carriers of known LQTS-causing mutations often exhibit incomplete penetrance, implicating genetic modifiers in the penetrance of disease. We identified a family with a novel mutation in the HERG potassium channel resulting in a "latent" form of LQTS. Only with the inheritance of a common HERG polymorphism on the second allele were clinical symptoms apparent. A second family exhibited both long and short QT intervals, previously thought to result from opposing functional mechanisms. Characterization of the novel HERG mutation revealed both gain-of-function and loss-of-function properties, mimicking the clinical presentation of the patient. We also investigated the ability of a family of potassium channel accessory subunits (KCNE1-5) to modulate IKs, a potassium current essential for cardiac repolarization. Each of the KCNE genes is expressed in the human heart, with effects on IKs ranging from stimulation to complete inhibition of potassium current. Characterization and screening of promoter regions revealed non-coding variants in KCNE1 that may influence penetrance of disease. In summary, we provided evidence that common polymorphisms and novel accessory proteins can modulate the activity of known LQTS genes, suggesting mechanisms for variable phenotypes. We also characterized the transcriptional control regions of several genes important in cardiac repolarization, facilitating future studies investigating non-coding variants in the penetrance of LQTS. |
