SCN4A Gene: Sodium Voltage-Gated Channel Alpha Subunit 4
Genetic insights into SCN4A-related neuromuscular disorders: from channelopathies to therapeutic targets
Gene Information Card
| Symbol | SCN4A |
|---|---|
| Full Name | sodium voltage-gated channel alpha subunit 4 |
| Gene Type | protein coding |
| Chromosomal Location | 17q23.3 |
| NCBI Gene ID | 6329 ncbi.nlm.nih.gov/gene/6329 |
| Ensembl ID | ENSG00000007314 |
| UniProt ID | P35499 |
| OMIM ID | 603967 |
| HGNC ID | 10591 |
| Aliases | Nav1.4, HYKPP, HYPP, CMS16, NAC1A, SCN4A1 |
Description
The SCN4A gene encodes the alpha subunit of the voltage-gated sodium channel Nav1.4, which is predominantly expressed in skeletal muscle. This channel is critical for the initiation and propagation of action potentials in muscle fibers, regulating muscle contraction and relaxation. Mutations in SCN4A can lead to a spectrum of neuromuscular disorders, including myotonia and periodic paralyses, by altering channel gating, ion conductance, or expression.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Hyperkalemic Periodic Paralysis (HYPP) | Gain-of-function mutations in SCN4A cause impaired channel inactivation, leading to persistent sodium influx and muscle hyperexcitability, resulting in episodes of muscle weakness. | ClinVar, OMIM |
| Hypokalemic Periodic Paralysis (HYKPP) | Loss-of-function mutations reduce sodium current density, causing membrane hypoexcitability and weakness during hypokalemic episodes. | ClinVar, OMIM |
| Paramyotonia Congenita (PMC) | Mutations cause cold-induced myotonia and paradoxical weakness due to defective channel inactivation, leading to prolonged depolarization. | ClinVar, OMIM |
| Potassium-Aggravated Myotonia (PAM) | Gain-of-function mutations enhance channel activation, leading to myotonia exacerbated by potassium intake. | ClinVar, OMIM |
| Congenital Myasthenic Syndrome 16 (CMS16) | Loss-of-function mutations impair neuromuscular transmission, causing fatigable weakness. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal Muscle | High (e.g., 1000+ nTPM) | Predominant expression |
| Heart | Low | Minimal expression |
| Brain | Low | Minimal expression |
| Liver | Not detected | No significant expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Skeletal Muscle Myotubes | High | Differentiated muscle cells show high expression |
| C2C12 (mouse myoblast) | High | Model for muscle differentiation |
| HEK293 (transfected) | Variable | Used for functional studies of SCN4A mutations |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Thr704Met | Missense | Common in HYPP | Gain-of-function: impaired inactivation |
| p.Arg672His | Missense | Common in HYKPP | Loss-of-function: reduced current |
| p.Arg1448Cys | Missense | Associated with PMC | Gain-of-function: slowed inactivation |
| p.Gly1306Glu | Missense | Associated with PAM | Gain-of-function: enhanced activation |
| p.Val781Ile | Missense | Rare | Uncertain; possibly loss-of-function |
Mutation functional classification
Loss of Function (LOF)
Mutations that reduce sodium current density or impair channel trafficking, leading to hypoexcitability (e.g., HYKPP).
Gain of Function (GOF)
Mutations that impair inactivation or enhance activation, causing persistent sodium influx and hyperexcitability (e.g., HYPP, PMC).
Dominant Negative (DN)
Some mutations may exert dominant-negative effects by co-assembling with wild-type subunits, reducing overall functional channel expression.
View complete mutation data：
Gene Ontology (GO)
| • voltage-gated sodium channel activity | • sodium ion binding |
| • ion channel complex | • plasma membrane |
| • action potential propagation | • muscle contraction |
Pathways
• Voltage-gated sodium channel pathway
• Skeletal muscle contraction
• Ion transport
• Neuronal action potential (though primarily muscle)
Protein Summary
The Nav1.4 protein is a large, multi-domain alpha subunit that forms a functional sodium channel when associated with beta subunits. It consists of four homologous domains (I-IV), each with six transmembrane segments (S1-S6). The S4 segments serve as voltage sensors, while the loop between domains III and IV forms the inactivation gate. Mutations in critical regions, such as the inactivation gate or voltage sensors, disrupt channel function and lead to disease.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SCN4A Knockout HEK293 Cell Line | EDJ-KQ5718 | Human | 6329 | Details Get a Quote |
| SCN4A Knockout HeLa Cell Line | EDJ-KQ54401 | Human | 6329 | Details Get a Quote |
| SCN4A Knockout A-549 Cell Line | EDJ-KQ62892 | Human | 6329 | Details Get a Quote |
| SCN4A Knockout HCT 116 Cell Line | EDJ-KQ71358 | Human | 6329 | Details Get a Quote |
| SCN4A Overexpression HEK293 Stable Cell Line | EDC90354 | Human | 6329 | Details Get a Quote |
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