KCNJ2

The KCNJ2 gene belongs to a large family of genes that produce 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 KCNJ2 protein are active in muscles used for movement (skeletal muscles) and heart (cardiac) muscle, where they transport potassium ions into cells. In skeletal muscle, these channels play an important role in the pattern of muscle tensing (contraction) and relaxation that allows the body to move. In the heart, the channels are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. Channels formed with the KCNJ2 protein may also be involved in bone development, but their role in this process is unclear.

Researchers have determined that a molecule called PIP2 must bind to channels made with the KCNJ2 protein for the channels to function normally. PIP2 activates the ion channel and helps stabilize it in an open state, which allows ions to flow across the cell membrane.

Andersen-Tawil syndrome - caused by mutations in the KCNJ2 gene

More than 20 mutations in the KCNJ2 gene have been identified in people with Andersen-Tawil syndrome. Most of these mutations change a single protein building block (amino acid) in the KCNJ2 protein.

Mutations in the KCNJ2 gene lead to the production of a nonfunctional potassium channel. Some mutations change the shape of the channel so it cannot transport potassium ions, while other mutations prevent the channels from being inserted correctly into the cell membrane. Many KCNJ2 mutations prevent PIP2 from effectively binding to and activating potassium channels. If the KCNJ2 protein is unable to bind to PIP2, the channels remain closed and potassium ions are unable to flow into the cell. Researchers believe that problems with PIP2 binding are a major cause of Andersen-Tawil syndrome.

A loss of channel function in skeletal and cardiac muscle cells disrupts the normal flow of potassium ions into these cells, resulting in episodes of muscle weakness (periodic paralysis) and an irregular heart rhythm. It is not known how mutations in the KCNJ2 gene contribute to developmental abnormalities of the head, face, and limbs often found in Andersen-Tawil syndrome.

short QT syndrome - caused by mutations in the KCNJ2 gene

A KCNJ2 mutation has also been identified in one family with a heart condition called short QT syndrome. This mutation changes a single amino acid in the KCNJ2 protein. Specifically, it replaces the amino acid aspartic acid with the amino acid asparagine at protein position 172 (written as Asp172Asn or D172N). This change disrupts the usual function of ion channels made with the KCNJ2 protein, increasing the channels' activity. By allowing more potassium ions to flow into cardiac muscle cells at a critical time during the heartbeat, the D172N mutation is likely responsible for the changes in heart rhythm found in short QT syndrome.

familial atrial fibrillation - associated with the KCNJ2 gene

A mutation in the KCNJ2 gene is associated with rare cases of an abnormal heart rhythm called familial atrial fibrillation. In one family with this condition, researchers have identified a mutation that replaces the amino acid valine with the amino acid isoleucine at position 93 of the protein made by the KCNJ2 gene (written as Val93Ile or V93I). In cardiac muscle cells, this mutation appears to increase the flow of potassium ions through the channel formed by the KCNJ2 protein. The enhanced ion transport may alter the heart's normal rhythm. Researchers are working to determine whether the V93I mutation is the direct cause of atrial fibrillation in this family.