UniProt functional annotation for Q99250



	UniProt functional annotation for Q99250

UniProt code: Q99250.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Mediates the voltage-dependent sodium ion permeability of excitable membranes. 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 (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity). {ECO:0000250|UniProtKB:B1AWN6, ECO:0000269|PubMed:1325650, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:28256214, ECO:0000269|PubMed:29844171}.

Subunit: Heterooligomer of a large alpha subunit and a smaller beta subunit. Heterooligomer with SCN2B or SCN4B; disulfide-linked. Heterooligomer with SCN1B or SCN3B; non-covalently linked. Interacts with NEDD4L. Interacts with CALM. Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin- Pre1a (PubMed:28428547). Interacts with the conotoxin KIIIA (PubMed:30765605). Interacts with the spider protoxin-II (PubMed:26894959). {ECO:0000269|PubMed:24297919, ECO:0000269|PubMed:24497506, ECO:0000269|PubMed:28428547, ECO:0000269|PubMed:30765605}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:1325650}; Multi-pass membrane protein {ECO:0000269|PubMed:1325650}.

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. {ECO:0000305}.

Ptm: May be ubiquitinated by NEDD4L; which would promote its endocytosis. {ECO:0000250}.

Ptm: Phosphorylation at Ser-1506 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents. {ECO:0000250}.

Ptm: Sumoylated at Lys-38. Sumoylation is induced by hypoxia, increases voltage-gated sodium current and mediates the early response to acute hypoxia in neurons. Sumoylated SCN2A is located at the cell membrane. {ECO:0000250|UniProtKB:P04775}.

Disease: Seizures, benign familial infantile, 3 (BFIS3) [MIM:607745]: 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. BFIS3 inheritance is autosomal dominant. {ECO:0000269|PubMed:11371648, ECO:0000269|PubMed:12243921, ECO:0000269|PubMed:15048894, ECO:0000269|PubMed:16417554, ECO:0000269|PubMed:17021166, ECO:0000269|PubMed:17386050, ECO:0000269|PubMed:18479388, ECO:0000269|PubMed:20371507, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:23360469, ECO:0000269|PubMed:23758435, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:29844171, ECO:0000269|PubMed:30144217}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Developmental and epileptic encephalopathy 11 (DEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:19783390, ECO:0000269|PubMed:19786696, ECO:0000269|PubMed:20956790, ECO:0000269|PubMed:22677033, ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23195492, ECO:0000269|PubMed:23550958, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:23935176, ECO:0000269|PubMed:23988467, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:24579881, ECO:0000269|PubMed:24659627, ECO:0000269|PubMed:24710820, ECO:0000269|PubMed:25457084, ECO:0000269|PubMed:25459969, ECO:0000269|PubMed:25772804, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:26291284, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:29625812, ECO:0000269|PubMed:29844171, ECO:0000269|PubMed:30144217, ECO:0000269|PubMed:30415926}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Note=Defects in SCN2A are associated with genetic epilepsy with febrile seizures plus (GEFS+), a familial autosomal dominant epilepsy syndrome, a clinical subset of febrile seizures, characterized by frequent episodes after 6 years of age and various types of subsequent epilepsy. {ECO:0000269|PubMed:29635106}.

Disease: Note=Defects in SCN2A are associated with autism spectrum disorders (ASD). It seems that mutations resulting in sodium channel gain of function and increased neuron excitability lead to infantile seizures, whereas variants resulting in sodium channel loss of function and decrease neuron excitability are associated with ASD. {ECO:0000269|PubMed:28256214}.

Disease: Episodic ataxia 9 (EA9) [MIM:618924]: An autosomal dominant neurologic disorder characterized by episodic ataxia manifesting in the first years of life, early-onset seizures, difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The duration of ataxic episodes is heterogeneous. Most patients show episodes lasting minutes to maximum several hours, but periods lasting days up to weeks have been reported. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. {ECO:0000269|PubMed:26645390, ECO:0000269|PubMed:27159988, ECO:0000269|PubMed:27328862, ECO:0000269|PubMed:28065826}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.2/SCN2A subfamily. {ECO:0000305}.

Sequence caution: Sequence=CAA46438.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAA46438.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Mediates the voltage-dependent sodium ion permeability of excitable membranes. 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 (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity). {ECO:0000250\|UniProtKB:B1AWN6, ECO:0000269\|PubMed:1325650, ECO:0000269\|PubMed:17021166, ECO:0000269\|PubMed:28256214, ECO:0000269\|PubMed:29844171}.


Subunit:		Heterooligomer of a large alpha subunit and a smaller beta subunit. Heterooligomer with SCN2B or SCN4B; disulfide-linked. Heterooligomer with SCN1B or SCN3B; non-covalently linked. Interacts with NEDD4L. Interacts with CALM. Interacts with the conotoxin GVIIJ (PubMed:24497506). Interacts with the spider beta/delta-theraphotoxin- Pre1a (PubMed:28428547). Interacts with the conotoxin KIIIA (PubMed:30765605). Interacts with the spider protoxin-II (PubMed:26894959). {ECO:0000269\|PubMed:24297919, ECO:0000269\|PubMed:24497506, ECO:0000269\|PubMed:28428547, ECO:0000269\|PubMed:30765605}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:1325650}; Multi-pass membrane protein {ECO:0000269\|PubMed:1325650}.
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. {ECO:0000305}.
Ptm:		May be ubiquitinated by NEDD4L; which would promote its endocytosis. {ECO:0000250}.
Ptm:		Phosphorylation at Ser-1506 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents. {ECO:0000250}.
Ptm:		Sumoylated at Lys-38. Sumoylation is induced by hypoxia, increases voltage-gated sodium current and mediates the early response to acute hypoxia in neurons. Sumoylated SCN2A is located at the cell membrane. {ECO:0000250\|UniProtKB:P04775}.
Disease:		Seizures, benign familial infantile, 3 (BFIS3) [MIM:607745]: 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. BFIS3 inheritance is autosomal dominant. {ECO:0000269\|PubMed:11371648, ECO:0000269\|PubMed:12243921, ECO:0000269\|PubMed:15048894, ECO:0000269\|PubMed:16417554, ECO:0000269\|PubMed:17021166, ECO:0000269\|PubMed:17386050, ECO:0000269\|PubMed:18479388, ECO:0000269\|PubMed:20371507, ECO:0000269\|PubMed:22612257, ECO:0000269\|PubMed:23360469, ECO:0000269\|PubMed:23758435, ECO:0000269\|PubMed:25982755, ECO:0000269\|PubMed:26291284, ECO:0000269\|PubMed:29844171, ECO:0000269\|PubMed:30144217}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Developmental and epileptic encephalopathy 11 (DEE11) [MIM:613721]: An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269\|PubMed:19783390, ECO:0000269\|PubMed:19786696, ECO:0000269\|PubMed:20956790, ECO:0000269\|PubMed:22677033, ECO:0000269\|PubMed:23033978, ECO:0000269\|PubMed:23195492, ECO:0000269\|PubMed:23550958, ECO:0000269\|PubMed:23662938, ECO:0000269\|PubMed:23708187, ECO:0000269\|PubMed:23935176, ECO:0000269\|PubMed:23988467, ECO:0000269\|PubMed:24463883, ECO:0000269\|PubMed:24579881, ECO:0000269\|PubMed:24659627, ECO:0000269\|PubMed:24710820, ECO:0000269\|PubMed:25457084, ECO:0000269\|PubMed:25459969, ECO:0000269\|PubMed:25772804, ECO:0000269\|PubMed:25818041, ECO:0000269\|PubMed:26138355, ECO:0000269\|PubMed:26291284, ECO:0000269\|PubMed:26993267, ECO:0000269\|PubMed:27864847, ECO:0000269\|PubMed:29625812, ECO:0000269\|PubMed:29844171, ECO:0000269\|PubMed:30144217, ECO:0000269\|PubMed:30415926}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Note=Defects in SCN2A are associated with genetic epilepsy with febrile seizures plus (GEFS+), a familial autosomal dominant epilepsy syndrome, a clinical subset of febrile seizures, characterized by frequent episodes after 6 years of age and various types of subsequent epilepsy. {ECO:0000269\|PubMed:29635106}.
Disease:		Note=Defects in SCN2A are associated with autism spectrum disorders (ASD). It seems that mutations resulting in sodium channel gain of function and increased neuron excitability lead to infantile seizures, whereas variants resulting in sodium channel loss of function and decrease neuron excitability are associated with ASD. {ECO:0000269\|PubMed:28256214}.
Disease:		Episodic ataxia 9 (EA9) [MIM:618924]: An autosomal dominant neurologic disorder characterized by episodic ataxia manifesting in the first years of life, early-onset seizures, difficulty walking, dizziness, slurred speech, headache, vomiting, and pain. The duration of ataxic episodes is heterogeneous. Most patients show episodes lasting minutes to maximum several hours, but periods lasting days up to weeks have been reported. Some patients have mildly delayed development with speech delay and/or autistic features or mildly impaired intellectual development. {ECO:0000269\|PubMed:26645390, ECO:0000269\|PubMed:27159988, ECO:0000269\|PubMed:27328862, ECO:0000269\|PubMed:28065826}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.2/SCN2A subfamily. {ECO:0000305}.
Sequence caution:		Sequence=CAA46438.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAA46438.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part.; Evidence={ECO:0000305};