Falcon deep research report for SCN1A
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Falcon corroborates SCN1A/Nav1.1 as the pore-forming voltage-gated sodium channel alpha subunit required for neuronal action potentials, with especially important function in GABAergic inhibitory interneurons.
"The UniProt accession **P35498** corresponds to **human SCN1A**, encoding the pore‑forming α subunit of the voltage‑gated sodium channel **NaV1.1**."
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Falcon supports the core neuronal excitability interpretation and distinguishes loss-of-function disease mechanism from direct GO molecular function annotation.
"The best-supported physiological role is enabling **high-frequency firing of inhibitory interneurons** and thereby maintaining **excitation-inhibition balance**."
Gene Ontology annotation through association of InterPro records with GO terms.
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
Automatic assignment of GO terms using logical inference, based on on inter-ontology links.
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods.
Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2.
Epilepsy-associated dysfunction in the voltage-gated neuronal sodium channel SCN1A.
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Experimental evidence for SCN1A voltage-gated sodium channel activity using mutant phenotype analysis
"We examined the functional properties of four GEFS+ alleles and one SMEI allele using whole-cell patch-clamp analysis of heterologously expressed recombinant human SCN1A"
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Demonstrates plasma membrane localization through direct experimental evidence
"Voltage-gated sodium channels are responsible for the generation and propagation of action potentials in excitable tissues"
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Shows membrane depolarization function during action potentials in neuronal excitability
"Mutations in genes encoding sodium channel pore-forming α subunits and an accessory β 1 subunit have been associated with disorders of membrane excitability"
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Establishes SCN1A as directly involved in action potential depolarization phase
"Our data provide evidence for a wide spectrum of sodium channel dysfunction in familial epilepsy and demonstrate that both GEFS+ and SMEI can be associated with nonfunctional SCN1A alleles"
Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations.
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Demonstrates that SCN1A truncating mutations cause Dravet syndrome through haploinsufficiency mechanism
"About 50% of SCN1A DS mutations truncate Na(V)1.1, possibly causing complete loss of its function"
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Confirms that mutant channels are not dominant negative, supporting pure loss-of-function pathogenesis
"Na(V)1.1 truncated mutants are not dominant negative, consistent with haploinsufficiency as the cause of DS"
Variants of Transient Receptor Potential Melastatin Member 4 in Childhood Atrioventricular Block.
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Study about TRPM4 variants, not directly related to SCN1A function - annotation may be erroneous
"Transient receptor potential melastatin member 4 (TRPM4) is a nonselective cation channel. TRPM4 mutations have been linked to cardiac conduction disease and Brugada syndrome"
SCN1A UniProt functional annotation
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Confirms 24-transmembrane domain architecture of Nav1.1 α-subunit
"TRANSMEM 129..146 ... TRANSMEM 153..177 ... TRANSMEM 189..205 ... TRANSMEM 214..235 ... TRANSMEM 246..269 ... TRANSMEM 398..423 ... TRANSMEM 769..787 ... TRANSMEM 798..820 ... TRANSMEM 831..849 ... TRANSMEM 855..874 ... TRANSMEM 892..912 ... TRANSMEM 966..992 ... TRANSMEM 1219..1237 ... TRANSMEM 1251..1276 ... TRANSMEM 1279..1304 ... TRANSMEM 1314..1332 ... TRANSMEM 1346..1369 ... TRANSMEM 1458..1483 ... TRANSMEM 1542..1560 ... TRANSMEM 1572..1593 ... TRANSMEM 1602..1623 ... TRANSMEM 1637..1655 ... TRANSMEM 1666..1688 ... TRANSMEM 1760..1788"
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Documents catalytic activity: Na+(in) = Na+(out) representing selective sodium transport
"CATALYTIC ACTIVITY: Reaction=Na(+)(in) = Na(+)(out)"
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Establishes role in action potential depolarization phase
"Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes"
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Notes contribution to sensory perception of mechanically-induced pain
"Nav1.1 plays a role in controlling the excitability and action potential propagation from somatosensory neurons, thereby contributing to the sensory perception of mechanically-induced pain"
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Confirms plasma membrane localization and voltage-gated channel complex formation
"SUBCELLULAR LOCATION: Cell membrane ... Multi-pass membrane protein"
SCN1A clinical significance in epilepsy genetics
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SCN1A is the most frequently mutated gene in genetic epilepsies
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Mutations found in >80% of Dravet syndrome cases representing the major genetic cause
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Phenotypic spectrum ranges from febrile seizures (GEFS+) to severe developmental epileptic encephalopathy
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Loss-of-function mutations preferentially affect GABAergic interneurons leading to network disinhibition
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Sodium channel blockers are contraindicated as they worsen seizures by further impairing interneuron function
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Associated with sudden unexpected death in epilepsy (SUDEP) in severe cases