Romano-Ward syndrome Mutations in the KCNH2 gene are a common cause of Romano-Ward syndrome, often called long QT syndrome. This condition causes the heart (cardiac) muscle to take longer than usual to recharge between beats, which can lead to an abnormal heart rhythm (arrhythmia). More than 500 KCNH2 gene mutations that cause Romano-Ward syndrome have been identified. Some of these mutations change a single protein building block (amino acid) in the KCNH2 protein, while other mutations delete several amino acids from the protein. These changes prevent the protein from assembling into functional ion channels or alter the channels' structure. As a result, the channels cannot properly regulate the flow of potassium ions in cardiac muscle cells. The reduced ion transport alters the transmission of electrical signals in the heart, increasing the risk of an irregular heartbeat that can cause fainting (syncope) or sudden death. short QT syndrome Mutations in the KCNH2 gene can also cause a heart condition called short QT syndrome. In people with this condition, the cardiac muscle takes less time than usual to recharge between beats. This change increases the risk of an abnormal heart rhythm that can cause syncope or sudden death. At least two mutations in the KCNH2 gene have been found to cause short QT syndrome in a small number of affected families. These mutations change single amino acids in the KCNH2 protein. The genetic changes alter the function of ion channels made with the KCNH2 protein, increasing the channels' activity. As a result, more potassium ions flow out of cardiac muscle cells at a critical time during the heartbeat, which can lead to an irregular heart rhythm. other disorders Certain drugs, including medications used to treat arrhythmias, infections, seizures, and psychotic disorders, can lead to an abnormal heart rhythm in some people. This drug-induced heart condition, which is known as acquired long QT syndrome, increases the risk of cardiac arrest and sudden death. A small percentage of cases of acquired long QT syndrome occur in people who have an underlying variation in the KCNH2 gene.

     The KCNH2 gene belongs to a large family of genes that provide instructions for making potassium channels. These channels, which transport positively charged atoms (ions) of potassium out of cells, play key roles in a cell's ability to generate and transmit electrical signals. The specific function of a potassium channel depends on its protein components and its location in the body. Channels made with the KCNH2 protein (also known as hERG1) are active in heart (cardiac) muscle. They are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. The KCNH2 protein is also produced in nerve cells and certain immune cells (microglia) in the central nervous system. The proteins produced from the KCNH2 gene and another gene, KCNE2, interact to form a functional potassium channel. Four alpha subunits, each produced from the KCNH2 gene, form the structure of each channel. One beta subunit, produced from the KCNE2 gene, attaches (binds) to the channel and regulates its activity.

The following transcription factors affect gene expression:

• NF-kappaB
• NF-kappaB1
• Sp1
• Nkx3-1 v1
• Nkx3-1

Tissue specificity:

Highly expressed in heart and brain. Isoforms USO are frequently overexpressed in cancer cells.

Induction:

Up-regulated by RNF207 (at protein level).

Molecular Function:

• Phosphorelay Sensor Kinase Activity
• Inward Rectifier Potassium Channel Activity
• Voltage-Gated Potassium Channel Activity
• Delayed Rectifier Potassium Channel Activity
• Ubiquitin Protein Ligase Binding
• Identical Protein Binding
• Protein Homodimerization Activity
• C3hc4-Type Ring Finger Domain Binding
• Voltage-Gated Potassium Channel Activity Involved In Cardiac Muscle Cell Action Potential Repolarization
• Scaffold Protein Binding
• Voltage-Gated Potassium Channel Activity Involved In Ventricular Cardiac Muscle Cell Action Potential Repolarization

Biological Processes:

• Regulation Of Heart Rate By Hormone
• Regulation Of Membrane Potential
• Potassium Ion Homeostasis
• Cardiac Muscle Contraction
• Regulation Of Membrane Repolarization
• Regulation Of Ventricular Cardiac Muscle Cell Membrane Repolarization
• Cardiac Conduction
• Potassium Ion Export
• Potassium Ion Transmembrane Transport
• Ventricular Cardiac Muscle Cell Action Potential
• Membrane Depolarization During Action Potential
• Membrane Repolarization During Action Potential
• Membrane Repolarization During Cardiac Muscle Cell Action Potential
• Regulation Of Heart Rate By Cardiac Conduction
• Potassium Ion Export Across Plasma Membrane
• Membrane Repolarization During Ventricular Cardiac Muscle Cell Action Potential
• Regulation Of Potassium Ion Transmembrane Transport
• Negative Regulation Of Potassium Ion Transmembrane Transport
• Positive Regulation Of Potassium Ion Transmembrane Transport
• Negative Regulation Of Potassium Ion Export

Drug Bank:

• Alfuzosin
• Amsacrine
• Astemizole
• Carvedilol
• Chlorpromazine
• Ciprofloxacin
• Cisapride
• Dofetilide
• Doxazosin
• Doxepin
• Dronedarone
• Erythromycin
• Halofantrine
• Imipramine
• Miconazole
• Pimozide
• Propafenone
• Sertindole
• Sotalol
• Terazosin
• Thioridazine
• Verapamil
• Amiodarone
• Clarithromycin
• Ibutilide
• Prazosin
• Quinidine