Sodium channel protein type 1 subunit alpha (SCN1A), is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
which in humans is encoded by the ''SCN1A''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Gene location
The SCN1A gene is located on chromosome 2 of humans, and is made up of 26 exons spanning a total length of 6030 nucleotide base pairs (bp).
Alternative splicing of exon 5 gives rise to two alternate exons. The promoter has been identified 2.5 kilobase pairs (kb) upstream of the transcription start site, and the 5'- untranslated exons may enhance expression of the SCN1A gene in SH-SY5Y cells, a human
cell line
An immortalised cell line is a population of cells from a multicellular organism which would normally not proliferate indefinitely but, due to mutation, have evaded normal cellular senescence and instead can keep undergoing division. The cell ...
derived from a
neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
.
Function
The vertebrate
sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
is a
voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, ...
essential for the generation and propagation of
action potential
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
s, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels.
Brain sodium channel alpha subunits form a gene subfamily with several structurally distinct isoforms clustering on chromosome 2q24, types I, II (
Nav1.2), and III (
Nav1.3). There are also several distinct sodium channel alpha subunit isoforms in skeletal and cardiac muscle (
Nav1.4 and
Nav1.5,
respectively).
The SCN1A gene codes for the
alpha subunit of the voltage-gated sodium ion channel making it a member of ten
paralogous
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...
gene families which code for the
voltage-gated sodium transmembrane proteins Na
V1.1. Within the family of genes which code for other portions of voltage-gated sodium channels, the SCN1A mutations were the first identified, since mutations to this gene caused epilepsy and febrile seizures. Indeed, the SCN1A gene is one of the most commonly mutated genes in the human genome associated with epilepsy, which has given it the title of a 'super culprit gene'. There are 900 distinct mutations reported for the SCN1A gene, approximately half of the reported mutations are truncations which result in no protein.
[Fujiwara, T., Sugawara, T., Mazaki‐Miyazaki, E., Takahashi, Y., Fukushima, K., Watanabe, M., … Inoue, Y. (2003). Mutations of sodium channel α subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic–clonic seizures. ''Brain'', ''126''(3), 531–546. https://doi.org/10.1093/brain/awg053] The remaining half of mutations are
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution.
Substitution of protein from DNA mutations
Missense m ...
s, which are predicted to either cause
loss-of-function or
gain-of-function
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host ran ...
, though very few have been tested for functionality in the lab.
Subtle differences in voltage-gated sodium ion channels can have devastating physiological effects and underlie abnormal neurological functioning. Mutations to the SCN1A gene most often result in different forms of seizure disorders, the most common forms of seizure disorders are Dravet Syndrome (DS), Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and severe myoclonic epilepsy borderline (SMEB).
Clinically, 70-80% of patients with DS have identified mutations specific to the SCN1A gene, which are caused by ''
de novo'' heterozygous mutations of the SCN1A gene. There are currently two databases on SCN1A mutations
Infobaseand th
SCN1A variant database
Mice with knock-in SCN1A mutations, who are model organisms for DS quickly develop seizures, indicative of a significant reduction in the function of Na
V1.1.
It has been hypothesized that reduced sodium currents due to Na
V1.1 mutations may cause hypoexcitability in
GABAergic inhibitory interneurons leading to epilepsy.
Mice in both the homozygous and heterozygous states develop the seizure phenotype and ataxia. Though homozygous mice die on average during the second to third week of life and approximately 50% of heterozygous null mice survive into adulthood.
[Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., … Catterall, W. A. (2006). Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience, 9(9), 1142–1149. https://doi.org/10.1038/nn1754]
Clinical significance
Mutations in the SCN1A gene cause inherited
febrile seizure
A febrile seizure, also known as a fever fit or febrile convulsion, is a seizure associated with an increased body temperature but without any intracranial infection. Febrile seizures affect 2–7% of children and are more common in boys than gi ...
s and
GEFS+, type 2.
Patent controversy
On 29 November 2008, The
Sydney Morning Herald
''The Sydney Morning Herald'' (''SMH'') is a daily compact newspaper published in Sydney, New South Wales, Australia, and owned by Nine. Founded in 1831 as the ''Sydney Herald'', the ''Herald'' is the oldest continuously published newspaper i ...
reported the first evidence of private intellectual property rights over human DNA
having adversely affected medical care. The Melbourne company Genetic Technologies (GTG) controls rights to the gene, and requires royalties for tests on the gene, which can help identify
Dravet syndrome
Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or feve ...
. Doctors on the Children's Hospital in
Westmead, Australia have told journalists that they would test 50% more infants for the gene, if they could conduct the test on site.
Interactions
Na
v1.1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
syntrophin, alpha 1
Alpha-1-syntrophin is a protein that in humans is encoded by the ''SNTA1'' gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Ple ...
.
See also
*
Sodium channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Familial Hemiplegic Migraine GeneReviews/NCBI/NIH/UW entry on SCN1A-Related Seizure Disorders*
{{NLM content
Sodium channels