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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001330260 27 - 11570 NP_001317189 - 1980 - 1997 9295353 neonatal exon 5N NM_001177984 25 - 6968 NP_001171455 - 1939 - 1998 9828131 adult exon 5A variant 5 - - - isoform 5 - - minor transcript 1997 9295353 splice donnor exon 10B 11 extra residues variant 4 - - - isoform 4 - - fetal neurons and non-neuronal cells 2009 19136557 neonatal exon 18N 18N includes a stop codon NM_014191 27 - 7215 NP_055006 - 1980 - 2009 19136557 adult exon 18A variant 6 26 - 5820 isoform 6 - 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Nervous brain forebrain cerebral lobe frontal lobe highly   brain hindbrain cerebellum       ganglia sensory ganglia dorsal root     Homo sapiens   spinal cord         Respiratory respiratory tract larynx     highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed neurology epilepsy   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 neurology epilepsy   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