 Hi, I'm Marika Osteber, a graduate student here at the Albert Einstein College of Medicine and first author on the recent article, An Interdomain Herg Mutation, produces an intermediate long QT phenotype that was published in the Human Mutation Journal. Here's an example of a normal lead of an electrocardiogram, or an ECG. This is the P-wave demonstrating atrial contraction. This is the QRS complex demonstrating ventricular contraction. And this is the T-wave demonstrating ventricular repolarization. In long QT syndrome, the heart has a hard time recovering from a beat, or repolarizing. As you can see here, the T-wave is longer, leading to a longer QT interval on the ECG. This finding is diagnostic for long QT syndrome and gives the syndrome its name. Let's now look at a single action potential for a ventricular cardiomyocyte. Here's the normal cardiomyocyte action potential. Sodium comes into the cell, stimulating depolarization, then potassium leaves and calcium comes in allowing for contraction, and then potassium leaves allowing for repolarization. This is an example of an action potential in long QT syndrome where repolarization time is increased. This can either be caused by too much sodium current or not enough potassium current. There are 13 known loci causative for long QT syndrome, but in this video we will be discussing the gene KCNH2. This gene is responsible for the protein HERG, which is the alpha subunit of a potassium channel responsible for the IKR current. In this article we investigated a mutation that was found in the HERG channel identified in one of our patients. This patient, who was a young boy of Southeast Asian descent, first came to our clinic because he'd experienced several syncopal or fainting episodes and in a local emergency room had a documented prolonged QT interval on electrocardiogram. Because the patient was adopted, we didn't have any family history and we recommended a genetic test to determine the cause of this long QT syndrome. The results from that test determined the patient had a mutation in the KCNH2 gene, which changed the 219th amino acid aspartate to the amino acid valine. The patient is now well maintained on medication and is stable, but since this mutation had not previously been reported as causative for long QT syndrome and was located in a domain of the protein that was sparse for other reported mutations, we determined that it was important to characterize the functional impact of this mutation. This is a cartoon representation of the HERG channel. This channel has six transmembrane domains, as well as a cytoplasmic N-terminal domain, which has a PAS domain, and a C-terminal domain, which contains a cyclic nucleotide binding domain. This mutation we describe in this article is located at the 219th amino acid past the PAS domain in the N-terminus. To make the potassium channel responsible for the IKR current, HERG tetramerizes. This creates a channel with a pore and allows for potassium to move from across the cell membrane. To determine the functional characteristics of the mutant HERG channel, we used electrophysiology techniques shown here to record the current of wild type, mutant, and 50-50 mixed channels. We looked at channel activation kinetics, inactivation kinetics, and deactivation kinetics to determine the differences between the wild type and the mutant channels. Through our investigation, we have determined that this area of the HERG channel plays the role in correct channel kinetics. This aspartate to valine mutation causes a rapid deactivation in comparison to the wild type, leading to reduced current during the cardiac action potential. Furthermore, these results point to a previously unknown function of this region of the IN channel. Thank you for watching our video highlight, and happy reading!