KCNQ1

The KCNQ1 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 into and out of cells, play a key role 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 KCNQ1 protein are active in the inner ear and in heart (cardiac) muscle, where they transport potassium ions out of cells. In the inner ear, these channels help maintain the proper ion balance needed for normal hearing. In the heart, the channels are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. The KCNQ1 protein is also produced in the kidney, lung, stomach, and intestine, where it is involved in transporting molecules across cell membranes.

The protein produced from the KCNQ1 gene interacts with proteins in the KCNE family (such as KCNE1) to form functional potassium channels. Four alpha subunits, each produced from the KCNQ1 gene, form the structure of each channel. One beta subunit, produced from a gene in the KCNE family, binds to the channel and regulates its activity.

Researchers believe that a molecule called PIP2 must bind to channels made with the KCNQ1 protein for the channels to function normally. PIP2 activates the ion channel and helps stabilize it when it is open, which allows ions to flow out of the cell.

familial atrial fibrillation - caused by mutations in the KCNQ1 gene

Changes in the KCNQ1 gene are an uncommon cause of an abnormal heart rhythm called familial atrial fibrillation. In one family with this condition, researchers have identified a mutation that changes a single protein building block (amino acid) used to make the KCNQ1 protein. Specifically, this genetic change replaces the amino acid serine with the amino acid glycine at protein position 140 (written as Ser140Gly or S140G). In cardiac muscle cells, this mutation appears to increase the flow of potassium ions through the channel formed by the KCNQ1 protein. The altered ion transport disrupts the heart's normal rhythm, resulting in atrial fibrillation.

Jervell and Lange-Nielsen syndrome - caused by mutations in the KCNQ1 gene

At least 12 KCNQ1 mutations that cause Jervell and Lange-Nielsen syndrome have been identified. Affected people typically have mutations in both copies of the KCNQ1 gene in each cell. Most of these changes lead to the production of a short, nonfunctional version of the KCNQ1 protein that cannot be used to build potassium channels. Other mutations alter a small number of amino acids in this protein, which alters the normal structure and function of the channels. At least one KCNQ1 mutation prevents PIP2 from effectively binding to and activating the channels, disrupting the normal flow of potassium ions across the cell membrane. An inability of cells in the inner ear and cardiac muscle to properly transport potassium ions leads to the hearing loss and abnormal heart rhythm (arrhythmia) found in Jervell and Lange-Nielsen syndrome.

Romano-Ward syndrome - caused by mutations in the KCNQ1 gene

Changes in the KCNQ1 gene are thought to be the most common cause of Romano-Ward syndrome, with more than 140 reported mutations. Unlike Jervell and Lange-Nielsen syndrome, people with Romano-Ward syndrome usually have a mutation in only one copy of the KCNQ1 gene in each cell. Most of these mutations change a single amino acid in the KCNQ1 protein or insert or delete a small number of amino acids. These changes allow the protein to form channels, but reduce the channels' ability to transport potassium ions out of cells. A small number of mutations disrupt the binding of PIP2 to the channels, which interferes with the normal flow of potassium ions across the cell membrane. A disruption in the flow of potassium ions in cardiac muscle results in the irregular heartbeat characteristic of Romano-Ward syndrome.

short QT syndrome - caused by mutations in the KCNQ1 gene

A mutation in the KCNQ1 gene has been associated with another heart condition called short QT syndrome. This genetic change replaces the amino acid valine with the amino acid leucine at protein position 307 (written as Val307Leu or V307L). This mutation disrupts the usual function of ion channels made with the KCNQ1 protein, increasing the channels' activity. By allowing more potassium ions to flow out of cardiac muscle cells at a critical time during the heartbeat, the V307L mutation is likely responsible for the changes in heart rhythm found in short QT syndrome.

other disorders - associated with the KCNQ1 gene

Mutations in the KCNQ1 gene are responsible for several other heart rhythm abnormalities including sudden infant death syndrome (SIDS) and acquired long QT syndrome.

SIDS is a major cause of death in babies younger than one year. It is characterized by sudden and unexplained death, usually during sleep. Although the cause of SIDS is often unknown, researchers have identified mutations in the KCNQ1 gene in a few cases of this condition. Other genetic and environmental factors, many of which have not been identified, also play a part in determining the risk of SIDS.

Certain drugs, including medications used to treat arrhythmias, infections, seizures, and psychotic disorders, can lead to another type of 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 mutation in the KCNQ1 gene.