SCN4A

The SCN4A gene belongs to a gene family, which provides the genetic sequence encoding the sodium channel component. These channels transport positively charged sodium ions into the cell and play a key role in the cell's ability to generate and transmit electrical signals. Among them, the SCN4A gene provides instructions for the production of the key part (α subunit) of sodium channels, which are abundant in skeletal muscle used for exercise. In order for muscles to move normally, these muscles must contract and relax in a coordinated manner. One of the changes that trigger muscle contraction is the flow of positively charged ions into muscle cells, for example, sodium ions. Among them, the function of the channel formed by the SCN4A protein is to control the entry of sodium ions into these cells.

Figure 1. Potential predictive value of SCN4A mutation status for immune checkpoint inhibitors in melanoma. (Weiyin Lin., et al.; 2020)

SCN4A Features

Wang et al. deduced the amino acid sequence of the SCN4A gene from adult skeletal muscle through cross-species polymerase chain reaction-mediated cloning and cDNA sequencing. The protein consists of 1,836 residues, and its sequence has 93% homology with the α subunit of adult rat skeletal muscle and 70% homology with the α subunit of other mammalian tissues. Further research found that the SCN4A gene is expressed in mouse skeletal muscle and brain and human cerebral cortex, which indicates that it has a role in neuronal tissue.

SCN4A and Disease

Hyperkalemic Periodic Paralysis

Clinical studies have found that more than 10 SCN4A gene mutations have been found to cause periodic hyperkalemia paralysis, which can lead to episodes of extreme muscle weakness, usually related to high potassium levels in the blood. These mutations change a single amino acid sequence in the SCN4A protein, thereby changing the structure and function of sodium channels in skeletal muscle cells. These changes delay or prevent the closure of the channel mediated by the SCN4A protein. Therefore, sodium ions continue to flow abnormally into muscle cells. The increase in sodium ions triggers the release of potassium ions from muscle cells, which causes more sodium channels to open, stimulating more sodium ions to flow into these cells. These changes in ion transmission reduce the ability of skeletal muscles to contract, leading to the onset of muscle weakness or paralysis.

Hypokalemic Periodic Paralysis

At least 7 mutations in the SCN4A gene have been found in patients with hypokalemic periodic paralysis, which can lead to episodes of extreme muscle weakness associated with low potassium levels in the blood (hypokalemia). SCN4A gene mutations account for about 10% of all cases. Every known mutation changes an amino acid in the SCN4A protein, thereby changing the structure and function of sodium channels in skeletal muscle cells. These abnormal channels change the normal flow of sodium ions, thereby preventing normal muscle contraction. Low potassium levels also cause this problem. Because exercise requires muscle contraction, these changes in ion transport lead to prolonged episodes of severe muscle weakness.

Paramyotonia Congenita

It is known that at least 18 mutations in the SCN4A gene can cause congenital paramyotonia, a muscle disease characterized by sustained muscle tension (myotonia), which prevents the muscles from relaxing normally. The mutation in the SCN4A gene that causes this condition changes an amino acid in the SCN4A protein, thereby changing the structure and function of sodium channels in skeletal muscle cells. The most common genetic change is the replacement of arginine with one of several other amino acids at position 1448 of the protein. The mutation delays the closing of the channels formed by the SCN4A protein, and once the channels are closed, it causes them to open again quickly. These changes increase the flux of sodium ions into skeletal muscle cells. The influx of extra sodium ions causes prolonged muscle contraction, which is characteristic of congenital smooth muscle rigidity. Muscles with persistently high sodium levels may not be able to contract at all, leading to attacks of muscle weakness. The effect of SCN4A gene mutations on altered ion channels may be enhanced by low temperature, which may help explain why exposure to cold causes symptoms and signs.

Potassium-aggravated Myotonia

Several mutations in the SCN4A gene cause potassium to increase muscle rigidity, which can cause muscle rigidity attacks and prevent the muscles from relaxing normally. The resulting muscle stiffness may be aggravated by eating potassium-rich foods. The most common genetic change associated with potassium aggravated myotonia is the replacement of glycine with one of several other amino acids at position 1306 of the protein. These mutations delay the closure of the SCN4A protein channel, which increases the flux of sodium ions into skeletal muscle cells. Excess potassium ions stimulate more sodium ions to flow into these cells. These changes in ion transmission trigger long-term muscle contraction, which is a characteristic of muscle stiffness that increases muscle rigidity by potassium.

Other Disorders

Mutations in the SCN4A gene also cause a congenital myasthenia syndrome, a muscle disorder that appears shortly after birth. People with this disease will experience general muscle weakness and recurrent paralysis, especially affecting the muscles used for speech and breathing. A related mutation in the SCN4A gene replaces valine with glutamate at position 1442 in the protein. This genetic change changes the structure and function of sodium channels in skeletal muscle cells. These channels are abnormally closed after repeated muscle contractions, reducing the flow of sodium ions into the muscle cells. This interruption of ion transport further reduces muscle contraction, leading to muscle weakness and paralysis.

References

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