sodium voltage-gated channel alpha subunit 1
The SCN1A 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 SCN1A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.1. These channels are primarily found in the brain, where they control the flow of sodium ions into cells. NaV1.1 channels are involved in transmitting signals from one nerve cell (neuron) to another. Communication between neurons depends on chemicals called neurotransmitters, which are released from one neuron and taken up by neighboring neurons. The flow of sodium ions through NaV1.1 channels helps determine when neurotransmitters will be released.
At least seven mutations in the SCN1A gene have been identified in people with familial hemiplegic migraine type 3 (FHM3), a form of migraine headache that runs in families. Each of these mutations changes a single protein building block (amino acid) in the NaV1.1 channel, which alters the channel's structure. The abnormal channels stay open longer than usual, which increases the flow of sodium ions into neurons. This increase triggers the cell to release more neurotransmitters. The resulting changes in signaling between neurons make people with FHM3 more susceptible to developing these severe headaches.
Hundreds of mutations in the SCN1A gene have been found to cause genetic epilepsy with febrile seizures plus (GEFS+), which is a spectrum of seizure disorders of varying severity. These conditions include simple febrile (fever-associated) seizures, which start in infancy and usually stop by age 5, and febrile seizures plus (FS+). FS+ involves febrile and other types of seizures, including those not related to fevers (afebrile seizures), that continue beyond childhood. The GEFS+ spectrum also includes other conditions, such as Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI), that cause more serious seizures that last longer and may be difficult to control. These recurrent seizures (epilepsy) can worsen over time and are often accompanied by a decline in brain function.
The SCN1A gene mutations that underlie GEFS+ have a variety of effects on the function of the NaV1.1 channel. Some mutations change single amino acids in the channel, which alter the channel's structure. Others lead to the production of a nonfunctional version of the NaV1.1 channel or reduce the number of these channels produced in each cell. Still other mutations change single amino acids in critical regions of the channel. All of these genetic changes affect the ability of NaV1.1 channels to transport sodium ions into neurons. Some mutations are thought to reduce channel activity while others may increase it. It is unclear, however, how these genetic changes underlie the development of seizures or why they lead to a range of seizure disorders with varying severity.
A common change (polymorphism) in the SCN1A gene has been associated with the effectiveness of certain anti-seizure medications. This polymorphism, which is written as ICS5N+5G>A, alters a single DNA building block (nucleotide) in the SCN1A gene. Studies suggest that this polymorphism is associated with the maximum safe amount (dose) of the anti-seizure drugs phenytoin and carbamazepine. These drugs treat epilepsy by blocking sodium channels (such as NaV1.1) in neurons. A dose that is too small may not control seizures effectively, while a dose that is too large may cause unwanted side effects. Researchers are hopeful that doctors will be able to test for the ICS5N+5G>A polymorphism to help determine the safest and most effective dose of anti-seizure medications for each individual.
This entry is adapted from https://medlineplus.gov/genetics/gene/scn1a