Human Gene SCN8A (ENST00000354534.6) from GENCODE V45lift37
Description: Homo sapiens sodium voltage-gated channel alpha subunit 8 (SCN8A), transcript variant 1, mRNA. (from RefSeq NM_014191) RefSeq Summary (NM_014191): This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]. Gencode Transcript: ENST00000354534.6 Gencode Gene: ENSG00000196876.9 Transcript (Including UTRs) Position: hg19 chr12:51,985,020-52,206,648 Size: 221,629 Total Exon Count: 27 Strand: + Coding Region Position: hg19 chr12:52,056,602-52,201,213 Size: 144,612 Coding Exon Count: 26
ID:SCN8A_HUMAN DESCRIPTION: RecName: Full=Sodium channel protein type 8 subunit alpha; AltName: Full=Sodium channel protein type VIII subunit alpha; AltName: Full=Voltage-gated sodium channel subunit alpha Nav1.6; FUNCTION: Mediates the voltage-dependent sodium ion permeability of excitable membranes (PubMed:29726066). Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. FUNCTION: [Isoform 5]: In macrophages and melanoma cells, may participate in the control of podosome and invadopodia formation. ACTIVITY REGULATION: Inhibited by tetrodotoxin and, more weakly, by its metabolite 4,9-ah-tetrodotoxin. SUBUNIT: The voltage-sensitive sodium channel consists of an ion- conducting pore-forming alpha subunit regulated by one or more beta-1 (SCN1B), beta-2 (SCN2B), beta-3 (SCN3B) and/or beta-4 (SCN4B) subunits. Beta-1 (SCN1B) and beta-3 (SCN3B) are non-covalently associated with alpha, while beta-2 (SCN2B) and beta-4 (SCN4B) are covalently linked by disulfide bonds. Interacts with NEDD4 and NEDD4L (By similarity). Interacts with FGF13 (PubMed:33245860). Interacts with FGF14, GBG3, GBB2 and SCN1B (PubMed:26900580). Interacts with TMEM233 (PubMed:37117223). Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin- Pre1a (PubMed:28428547). Interacts with CALM1; the interaction modulates the inactivation rate of SCN8A (By similarity). INTERACTION: Q9UQD0; Q92915-2: FGF14; NbExp=3; IntAct=EBI-2682072, EBI-12836320; SUBCELLULAR LOCATION: Cell membrane ; Multi-pass membrane protein Cell projection, axon Note=Mainly localizes to the axon initial segment. SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasmic vesicle. Note=Some vesicles are localized adjacent to melanoma invadopodia and macrophage podosomes. Does not localize to the plasma membrane. TISSUE SPECIFICITY: Expressed in the hippocampus with increased expression in epileptic tissue compared to normal adjacent tissue (at protein level) (PubMed:28842554). Isoform 5: Expressed in non-neuronal tissues, such as monocytes/macrophages. INDUCTION: Up-regulated in the hippocampus after epilepsy. DOMAIN: The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position. PTM: May be ubiquitinated by NEDD4L; which would promote its endocytosis. PTM: Phosphorylation at Ser-1497 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents. DISEASE: Cognitive impairment with or without cerebellar ataxia (CIAT) [MIM:614306]: A disorder characterized by markedly delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia. Features include bilateral esophoria, strabismatic amblyopia, unsustained gaze evoked nystagmus on horizontal gaze, ataxic gait, dysmetria in the upper limbs and dysarthria, with normal strength, tone, and reflexes. Note=The disease is caused by variants affecting the gene represented in this entry. DISEASE: Developmental and epileptic encephalopathy 13 (DEE13) [MIM:614558]: A form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. DEE13 is a severe form consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. te=The disease is caused by variants affecting the gene represented in this entry. DISEASE: Seizures, benign familial infantile, 5 (BFIS5) [MIM:617080]: A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS5 inheritance is autosomal dominant. te=The disease is caused by variants affecting the gene represented in this entry. DISEASE: Myoclonus, familial, 2 (MYOCL2) [MIM:618364]: An autosomal dominant neurologic disorder characterized by upper limb isolated myoclonus without seizures or cognitive impairment. MYOCL2 is a non- progressive disease with onset in the first decade of life. Note=The disease may be caused by variants affecting the gene represented in this entry. SIMILARITY: Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.6/SCN8A subfamily.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00520 - Ion transport protein PF00612 - IQ calmodulin-binding motif PF06512 - Sodium ion transport-associated PF11933 - Cytoplasmic domain of voltage-gated Na+ ion channel
ModBase Predicted Comparative 3D Structure on Q9UQD0
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Gene Ontology (GO) Annotations with Structured Vocabulary
Biological Process: GO:0006811 ion transport GO:0006814 sodium ion transport GO:0007399 nervous system development GO:0007422 peripheral nervous system development GO:0019228 neuronal action potential GO:0034765 regulation of ion transmembrane transport GO:0035725 sodium ion transmembrane transport GO:0042552 myelination GO:0055085 transmembrane transport GO:0086010 membrane depolarization during action potential