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FLASH GENE
Symbol SCN8A contributors: mct - updated : 15-03-2018
HGNC name sodium channel, voltage gated, type VIII, alpha subunit
HGNC id 10596
Corresponding disease
CAAMR cerebellar atrophy, ataxia, mental retardation
EIEE13 Epileptic encephalopathy, early infantile 13
Location 12q13.13      Physical location : 51.985.019 - 52.202.297
Synonym name
  • motor endplate disease
  • voltage-gated sodium channel Nav1.6
  • hNa6/Scn8a voltage-gated sodium channel
  • Synonym symbol(s) Nav1.6, NaCh6, PN4, CerIII, MED, BFIS5, CIAT, EIEE13
    DNA
    TYPE functioning gene
    STRUCTURE 217.29 kb     27 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    cytosine-phosphate-guanine/HTF
    motif repetitive sequence   long interspersed repetitive elements
    text structure
  • promoter with an L1 LINE elemnt and a MIR class SINE element
  • 8 consensus Sp1 binding sites and 2 INR binding sites
  • 2 consensus polyadenylation signals (AATAAA) downstream of the translation termination codon in exon 24
  • four untranslated exons 1a, 1b, 1c,1d, 71kb upstream the first coding exon
  • evolutionarily conserved, functional noncoding elements in the promoter region (Drews 2007)
  • MAPPING cloned Y linked   status confirmed
    Physical map
    MGC57341 12q13.13 hypothetical protein MGC57341 DKFZP586A0522 12q13.13 DKFZP586A0522 protein SLC11A2 12q13.1 solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 HCCR1 12q13.13 cervical cancer 1 protooncogene C12orf22 12q13.11-q13.12 chromosome 12 open reading frame 22 TFCP2 12q13.1 transcription factor CP2 POU6F1 12q13.1 POU domain, class 6, transcription factor 1 DAZAP2 2q33-q34 DAZ associated protein 2 LOC57228 12q13.13 hypothetical protein from clone 643 BIN2 4q22.1 bridging integrator 2 ELA1 12q13 elastase 1, pancreatic GALNT6 12q13 UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6) LOC387857 12 LOC387857 SLC4A8 12q13 solute carrier family 4, sodium bicarbonate cotransporter, member 8 SCN8A 12q13 sodium channel, voltage gated, type VIII, alpha FLJ33996 12q13.13 hypothetical protein FLJ33996 DKFZp686O1689 12q13.13 hypothetical protein DKFZp686O1689 ACVRL1 12q13 activin A receptor type II-like 1 ACVR1B 12q13 activin A receptor, type IB GRASP 12q13.13 GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein NR4A1 12q13 nuclear receptor subfamily 4, group A, member 1 FLJ11773 12q13.13 hypothetical protein FLJ11773 OR7E47P 12q13.13 olfactory receptor, family 7, subfamily E, member 47 pseudogene LOC144501 12q13.13 hypothetical protein LOC144501 LOC283403 12q13.13 hypothetical protein LOC283403
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    27 - 11570 - 1980 - 1997 9295353
  • neonatal
  • exon 5N
  • 25 - 6968 - 1939 - 1998 9828131
  • adult
  • exon 5A
  • - - - - - minor transcript 1997 9295353
  • splice donnor exon 10B
  • 11 extra residues
  • - - - - - fetal neurons and non-neuronal cells 2009 19136557
  • neonatal
  • exon 18N
  • 18N includes a stop codon
  • 27 - 7215 - 1980 - 2009 19136557
  • adult
  • exon 18A
  • 26 - 5820 - 1939 expressed at a low level in fetal neurons and many non-neural tissues 2009 19136557
  • lack exon 18
  • regulates cellular invasion through its effects on podosome and invadopodia formation in macrophages and melanoma cells
  • macrophages can express a full-length variant of NaV1.6 through deletion of exon 18
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Nervousbrainforebraincerebral lobefrontal lobehighly
     brainhindbraincerebellum  
     gangliasensory gangliadorsal root   Homo sapiens
     spinal cord    
    Respiratoryrespiratory tractlarynx  highly
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text central, peripherous and sympathetic nervous system
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four transmembrane domains of homology, each with six alpha helical membrane spanning segments
  • two cytoplasmic loops
  • a pore-forming and voltage-sensitive domain of the channel
  • several consensus sites for phosphorylation of serine and threonine residues conserved in other sodium channel family members
  • a IQ motif of SCN8A adopting an alpha-helical conformation in its interaction with the C-lobe of CALM1
  • HOMOLOGY
    interspecies homolog to murine Scn8a
    Homologene
    FAMILY
  • sodium channel family
  • CATEGORY transport channel
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,cytosolic,vesicle
    text localized in axonic, dendritic, presynaptic, and postsynaptic membranes
    basic FUNCTION
  • may be involved in producing the resurgent sodium current observed in cerebellar Purkinje cells
  • major neuronal sodium channel gene expressed throughout the central and peripheral nervous systems
  • having unique properties, together with the resurgent currents that they conduct in neurons, providing the driving force for sustained repetitive firing, a crucial property of neurons
  • is essential for neuronal excitability in central and peripheral nervous systems
  • likely augments signaling in cone bipolar cells
  • plays an important role in propagating action potentials along myelinated axons
  • hippocampus is an important structure in the mediation of SCN8A-dependent seizure protection
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • protein constituent of membrane
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • function as a genetic modifier of SCN1A
  • phosphorylation of the Pro-Gly-Ser-Pro motif within L1 of SCN8A is necessary for stress-induced current modulation, with positive or negative regulation depending upon the availability of the C-terminal Pro-Ser-Tyr motif to bind NEDD4L
  • MAP1B facilitates trafficking of SCNA8 to the neuronal cell surface
  • PUM2 is able to directly bind the predominant SCN8A expressed in pyramidal neurons and, through doing so, regulates translation of this key determinant of membrane excitability
  • CALM1 is known to modulate the inactivation kinetics of SCN8A by interacting with its IQ motif
  • APP enhances SCN8A sodium channel cell surface expression through a Go-coupled JNK pathway
  • FGF14 binds directly to SCN8A C-tail, regulating channel gating and expression, properties that are required for intrinsic excitability in neurons
  • RER1 controls the assembly and transport of SCN1A, SCN8A, the principal sodium channels responsible for recurrent firing, in Purkinje cell (PC)
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) CAAMR , EIEE13
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional somatic mutation      
    mutated in motor end-plate disease
    constitutional germinal mutation      
    associated with cognitive deficits and neuropsychiatric illness
    constitutional     --over  
    aberrant overexpression of SCN8A in limbic structures may contribute to some epilepsies, including temporal lobe epilepsy
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyepilepsy 
    blocking SCN8A channels may be one of the therapeutic benefits of currently used non-selective sodium channel-blocking anti-epileptic drugs, and may improve efficacy in patients with epilepsy
    neurologyepilepsy 
    potential of selectively targeting SCN8A for the treatment of refractory epilepsy
    ANIMAL & CELL MODELS
  • spontaneous mouse mutation, Scn8a(9J), that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia
  • Scn8a mutant mice have reduced function in both rod and the cone retinal pathways