SCN9A

The SCN9A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN9A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.7. The NaV1.7 sodium channels are found in specific nerve cells called nociceptors, which are involved in transmitting pain signals. Specifically, the nociceptors are located in areas originating near the spinal cord known as the dorsal root ganglion and sympathetic ganglion, which are essential for transmitting pain signals from the spinal cord to the brain.

erythromelalgia - caused by mutations in the SCN9A gene

At least 10 mutations in the SCN9A gene have been found to cause erythromelalgia. All identified mutations change one protein building block (amino acid) in the NaV1.7 sodium channel. These mutations result in a NaV1.7 sodium channel that opens more easily than usual and stays open longer than normal, increasing the flow of sodium ions that produce nerve impulses within nociceptors. This increase in sodium ions enhances transmission of pain signals, leading to the signs and symptoms of erythromelalgia.

other disorders - caused by mutations in the SCN9A gene

Mutations in the SCN9A gene can also cause channelopathy-associated insensitivity to pain. People with this condition cannot perceive physical pain. Affected individuals can tell the difference between sharp and dull and hot and cold, but cannot sense, for example, that a hot beverage is burning their tongue. Young children with this condition may sustain mouth or finger wounds due to repeated self-biting and may also have multiple burn-related injuries. The SCN9A mutations that cause channelopathy-associated insensitivity to pain result in the production of an abnormally short, nonfunctional NaV1.7 sodium channel. A lack of these channels impairs the transmission of pain signals, causing those affected with this condition to be insensitive to pain.

Other mutations in the SCN9A gene cause paroxysmal extreme pain disorder, a condition characterized by skin flushing and attacks of severe pain, most commonly in the areas around the eye, jaw, or rectum. The area of flushing typically corresponds to the site of the pain. The pain attacks are usually triggered by bowel movements, eating, or changes in temperature. The duration of the attacks varies from a few seconds to an hour or more. Most affected individuals experience tonic nonepileptic seizures that cause their entire body to become stiff or rigid. Some may have fainting spells and a slow heart rate. The symptoms of this disorder usually begin in infancy and persist throughout life. Mutations in the SCN9A gene that cause paroxysmal extreme pain disorder lead to a NaV1.7 sodium channel that cannot close as quickly as usual, causing prolonged transmission of pain signals.