SCN4A

The SCN4A 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 SCN4A gene provides instructions for making sodium channels that are abundant in muscles used for movement (skeletal muscles). For the body to move normally, these muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of certain ions, including sodium, into muscle cells. Channels made with the SCN4A protein control the flow of sodium ions into these cells.

hyperkalemic periodic paralysis - caused by mutations in the SCN4A gene

More than 10 mutations in the SCN4A gene are responsible for hyperkalemic periodic paralysis. Each of these mutations changes a single building block (amino acid) in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. These changes delay the closing of channels made with the SCN4A protein or prevent the channels from staying closed. As a result, sodium ions continue flowing into muscle cells abnormally. Muscles with sustained high levels of sodium ions are unable to contract, resulting in attacks of muscle weakness.

hypokalemic periodic paralysis - caused by mutations in the SCN4A gene

At least six mutations in the SCN4A gene have been identified in people with hypokalemic periodic paralysis. These genetic changes are responsible for about 10 percent of all cases of this condition. Each of the known mutations changes a single amino acid in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. The channels close too quickly, reducing the flow of sodium ions into muscle cells. This disruption in ion transport prevents muscles from contracting normally. Because muscle contraction is needed for movement, reduced sodium ion flow into muscle cells leads to episodes of severe muscle weakness or paralysis.

paramyotonia congenita - caused by mutations in the SCN4A gene

At least 13 mutations in the SCN4A gene are known to cause paramyotonia congenita. These mutations each change a single amino acid in the SCN4A protein, which alters the structure and function of sodium channels in skeletal muscle cells. The most common genetic changes replace the amino acid arginine with one of several other amino acids at protein position 1448.

Mutations delay the closing of channels made with the SCN4A protein and, once the channels are closed, cause them to open again too quickly. These changes increase the flow of sodium ions into skeletal muscle cells. An influx of extra sodium ions triggers prolonged muscle contractions, which underlie the episodes of muscle stiffness (myotonia) characteristic of paramyotonia congenita. Muscles with sustained high levels of sodium ions may become unable to contract at all, resulting in attacks of muscle weakness.

The effects of SCN4A mutations on the altered ion channels may be exacerbated by cold temperatures, which may help explain why signs and symptoms can be induced by exposure to cold.

potassium-aggravated myotonia - caused by mutations in the SCN4A gene

Several mutations in the SCN4A gene cause potassium-aggravated myotonia. The most common genetic changes replace the amino acid glycine with one of several other amino acids at protein position 1306. These mutations delay the closing of channels made with the SCN4A protein, which increases the flow of sodium ions into skeletal muscle cells. An influx of extra sodium ions triggers prolonged muscle contractions, which underlie the muscle stiffness characteristic of potassium-aggravated myotonia.

other disorders - caused by mutations in the SCN4A gene

A mutation in the SCN4A gene is also responsible for one form of congenital myasthenic syndrome, a muscle disorder that appears shortly after birth. People with this disorder have general muscle weakness and recurrent attacks of paralysis that specifically affect muscles used for speaking and breathing. The SCN4A mutation associated with this condition replaces the amino acid valine with the amino acid glutamic acid at protein position 1442 (written as Val1442Glu or V1442E). This genetic change alters the structure and function of sodium channels in skeletal muscle cells. The channels close too quickly, reducing the flow of sodium ions into muscle cells. This disruption in ion transport interferes with normal muscle contraction, leading to muscle weakness and episodes of paralysis.