Alternative titles; symbols
HGNC Approved Gene Symbol: SCN1A
SNOMEDCT: 230437002; ICD10CM: G40.83, G40.834;
Cytogenetic location: 2q24.3 Genomic coordinates (GRCh38) : 2:165,984,641-166,149,161 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q24.3 | Developmental and epileptic encephalopathy 6B, non-Dravet | 619317 | Autosomal dominant | 3 |
| Dravet syndrome | 607208 | Autosomal dominant | 3 | |
| Febrile seizures, familial, 3A | 604403 | Autosomal dominant | 3 | |
| Generalized epilepsy with febrile seizures plus, type 2 | 604403 | Autosomal dominant | 3 | |
| Migraine, familial hemiplegic, 3 | 609634 | Autosomal dominant | 3 |
The vertebrate sodium channel is a voltage-gated ion channel essential for the generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large central pore-forming glycosylated alpha subunit and 2 smaller auxiliary beta subunits. Functional studies have indicated that the transmembrane alpha subunit of the brain sodium channels is sufficient for expression of functional sodium channels (Goldin et al., 1986; Isom, 2002).
Escayg et al. (2000) determined the coding sequence of the human SCN1A gene by aligning the rat cDNA sequence with genomic sequence. The deduced amino acid sequence of the 2,009-residue human SCN1A protein was determined. Human SCN1A is highly conserved, with 98% amino acid sequence identity to the corresponding rat sequence.
Escayg et al. (2000) determined that the SCN1A gene has 26 exons. Its intron-exon organization is identical to that of SCN8A (600702) at chromosome 12q13 and probably corresponds to that of the ancestral gene.
In the mouse, Malo et al. (1991) showed that Scn1a and Scn2a are tightly linked and separated by a distance of 0.7 cM. The latter gene (SCN2A; 182390) had been mapped to chromosome 2 in both man and mouse; by homology, SCN1A would be located on human chromosome 2.
By fluorescence in situ hybridization, Malo et al. (1994, 1994) mapped the SCN1A gene to chromosome 2q24. Escayg et al. (2000) confirmed the location of SCN1A within the candidate region for generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403) by typing the GB4 radiation hybrid panel with primers for intron 21, further localizing the SCN1A gene to the 4-cM interval between D2S156 and D2S399.
The axon initial segment (AIS) is the site at which neural signals arise, and should be the most efficient site to regulate neural activity. Kuba et al. (2010) reported that deprivation of auditory input in an avian brainstem auditory neuron leads to an increase in AIS length, thus augmenting the excitability of the neuron. The length of the AIS, defined by the distribution of voltage-gated sodium channels and the AIS anchoring protein, ankyrin G (106410), increased by 1.7 times in 7 days after auditory input deprivation. This was accompanied by an increase in the whole-cell sodium current, membrane excitability, and spontaneous firing. Kuba et al. (2010) concluded that their work demonstrated homeostatic regulations of the AIS, which may contribute to the maintenance of the auditory pathway after hearing loss. Furthermore, plasticity at the spike initiation site suggests a powerful pathway for refining neuronal computation in the face of strong sensory deprivation.
Osteen et al. (2016) identified and characterized tarantula toxins that selectively activated human and rodent NAV1.1. Using the spider toxin probes in mice, they showed that activated Nav1.1-expressing fibers elicited robust pain behavior without neurogenic inflammation and produced profound hypersensitivity to mechanical, but not thermal, stimuli. Mechanosensitive fibers expressing Nav1.1 were also present in gut and showed enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Osteen et al. (2016) concluded that NAV1.1 contributes to peripheral pain signaling, by both acute and repetitive mechanical stimulation, through myelinated afferent fibers expressing the receptor.
Mulley et al. (2005) stated that of all the known epilepsy genes, SCN1A was the most clinically relevant, with the largest number of epilepsy-related mutations characterized to that time.
Generalized Epilepsy with Febrile Seizures Plus, Type 2
Baulac et al. (1999) and Moulard et al. (1999) reported 2 unrelated families with generalized epilepsy with febrile seizures plus who showed linkage to a locus on chromosome 2q21-q33, consistent with GEFS+ type 2 (GEFSP2; 604403). Using conformation-sensitive gel electrophoresis to scan the 26 exons of the SCN1A gene from 1 affected and 1 unaffected individual from each of these families, Escayg et al. (2000) identified 2 missense mutations. The mutant residues thr875 (see 182389.0002) and arg1648 (see 182389.0001) are located in the S4 transmembrane segments of the sodium channel alpha-subunit, which is composed of 4 homologous domains (D1-D4), each containing 6 transmembrane segments. The functional importance of the mutations was supported by the evolutionary conservation in other mammalian gene family members and in lower vertebrates and invertebrates.
Escayg et al. (2001) identified an additional SCN1A mutation (W1204R; 182389.0006) in a family with GEFS+2, but concluded that SCN1A is not a major contributor to idiopathic generalized epilepsy (EIG; 600669).
In affected members of 3 unrelated families with GEFS+2, Wallace et al. (2001) identified heterozygous missense mutations in the SCN1A gene: family A, the Australian family originally reported by Scheffer and Berkovic (1997), had a D188V mutation (182389.0003); family B, of Ashkenazi Jewish descent, had a V1353L mutation (182389.0004); and family C, of Druze origin, carried an I1656M mutation (182389.0005). Functional studies of the variants and studies of patient cells were not performed, but the authors noted that all occurred in functional domains and may result in neuronal hyperexcitability.
Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (600235), and no mutations were found in the GABRG2 gene (137164).
Dravet Syndrome
Mutation in the SCN1A gene can cause a spectrum of early-onset epileptic encephalopathies, with the most common designation being Dravet syndrome (DRVT; 607208) (summary by Carranza Rojo et al., 2011).
Because both GEFS+ and Dravet syndrome, also known as severe myoclonic epilepsy of infancy (SMEI), involve fever-associated seizures, and because GEFS+ is associated with mutations in the SCN1A gene, Claes et al. (2001) screened 7 unrelated Belgian patients with SMEI for mutations in SCN1A. They identified de novo heterozygous mutations in each patient (see, e.g., 182389.0007-182389.0009). The mutations included 4 frameshifts, 1 nonsense, 1 splice site, and 1 missense. Functional studies of the variant and studies of patient cells were not performed.
In 14 patients, including a pair of monozygotic twins, with classic symptoms of SMEI, Sugawara et al. (2002) identified 10 heterozygous mutations in the SCN1A gene. There were 3 frameshift mutations that resulted in intragenic stop codons and truncated channels, and 7 nonsense mutations which also resulted in truncated channels.
In 29 patients with severe myoclonic epilepsy of infancy and 11 patients with other types of epilepsy, Ohmori et al. (2002) performed a mutation search of the SCN1A gene. They detected de novo heterozygous mutations in 24 of the 29 patients with SMEI, but in none of the patients with other types of epilepsy. The mutations included deletions, insertions, missense changes, and nonsense changes. The authors found no mutations in the SCN1B or GABRG2 (137164) genes.
Claes et al. (2003) investigated 9 patients with Dravet syndrome and observed 8 coding and 1 noncoding mutation in the SCN1A gene. In contrast to a previous study of 7 isolated patients (Claes et al., 2001), most mutations were found to be missense mutations clustering in the S4-S6 region of SCN1A. These findings demonstrated that de novo mutations in SCN1A are a major cause of isolated Dravet syndrome.
In 7 of 10 unrelated patients with intractable childhood epilepsy with generalized tonic-clonic seizures, a variant of Dravet syndrome without myoclonus, Fujiwara et al. (2003) identified heterozygous mutations in the SCN1A gene (see, e.g., 182389.0013; 182389.0014). All of the mutations were missense mutations. The findings extended the phenotypic spectrum associated with mutations in the SCN1A gene.
Using multiplex ligation-dependent probe amplification (MLPA), Mulley et al. (2006) identified exon deletions in the SCN1A gene (182389.0018 and 182389.0019) in 2 (15%) of 13 unrelated SMEI patients who did not have point or splice site mutations in the SCN1A gene. The findings provided a new molecular mechanism for the disorder.
Zucca et al. (2008) identified 13 mutations, including 12 novel mutations, in the SCN1A gene in 12 (20%) of 60 unrelated patients with cryptogenic epilepsy beginning in the first 2 years of life. Ten patients had SMEI, and 1 had GEFS+. The twelfth patient had severe mental retardation and generalized tonic-clonic seizures, which evolved to hemiclonic seizures suggestive of focal epilepsy; this phenotype was considered to be a variable expression of SMEI. No large deletions in the SCN1A gene were identified.
Depienne et al. (2009) identified pathogenic mutations or deletions, including 161 novel point mutations, in the SCN1A gene in 242 (73%) of 333 patients with Dravet syndrome. The most common mutations were missense (42%), and 14 patients had microrearrangements in or deletions of the gene. Thus, the disease mechanism appeared to be haploinsufficiency of the SCN1A gene. Mutations were scattered throughout the gene, and there were no apparent genotype/phenotype correlations.
Orrico et al. (2009) identified 21 mutations, including 14 novel mutations, in the SCN1A gene in 22 (14.66%) of 150 Italian pediatric probands with epilepsy. SCN1A mutations were found in 21.2% of patients with GEFS+ and in 75% of patients with Dravet syndrome from the overall patient cohort. Only 1 potentially pathogenic mutation was identified in the SCN1B gene (600235), and no mutations were found in the GABRG2 gene (137164).
Singh et al. (2009) presented preliminary evidence that mutations in the SCN9A gene (603415) may act as a genetic modifier of Dravet syndrome when found in conjunction with an SCN1A mutation. They identified mutations in the SCN9A gene in 9 (8%) of 109 patients with Dravet syndrome, including 6 with SCN1A mutation and 3 without SCN1A mutation.
Using Western blot analysis and ELISA, Thompson et al. (2012) showed that 7 different nontruncating SCN1A mutations associated with SMEI, including R1648C, impaired trafficking of SCN1A and reduced its cell surface expression. Treatment with the antiepileptic drugs phenytoin or lamotrigine increased the cell surface expression of R1648C and restored its voltage-gated sodium channel function. However, lamotrigine also increased persistent sodium current mediated by R1648C. Phenytoin increased surface expression of another mutant channel but did not restore its channel function, suggesting that some SCN1A mutations also cause intrinsic loss of function.
Familial Hemiplegic Migraine 3
In affected members of 3 European families with familial hemiplegic migraine-3 (FHM3; 609634), Dichgans et al. (2005) identified a heterozygous mutation in the SCN1A gene (182389.0012).
Familial Febrile Seizures 3A
In affected members of an Italian family with familial febrile convulsions-3A (FEB3A; see 604403), Mantegazza et al. (2005) identified heterozygosity for a mutation in the SCN1A gene (182389.0015).
Developmental and Epileptic Encephalopathy 6B
In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Ohashi et al. (2014) identified a de novo heterozygous missense mutation in the SCN1A gene (V422L; 182389.0025). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed.
In 8 unrelated patients with DEE6B, Sadleir et al. (2017) identified a de novo recurrent heterozygous missense mutation in the SCN1A gene (T226M; 182389.0026). Another patient (patient 9) carried a different de novo heterozygous missense mutation (P1345S; 182389.0027). Functional studies of the variants were not performed, but the authors speculated a gain-of-function effect.
Studies of SCN1A Protein Variants
Lossin et al. (2002) characterized the functional effects of 3 mutations in SCN1A by heterologous expression with its accessory subunits, SCN1B and SCN2B (601327), in cultured mammalian cells. SCN1A mutations altered channel inactivation, resulting in persistent inward sodium current. This gain-of-function abnormality was expected to enhance excitability of neuronal membranes by causing prolonged membrane depolarization, a plausible underlying biophysical mechanism responsible for autosomal dominant generalized epilepsy with febrile seizures plus.
Tate et al. (2005) identified a G-to-A polymorphism in the SCN1A gene (rs3812718; 182389.0016) that affects alternative splicing of exon 5. The major A allele disrupts the consensus sequence of the fetal/neonatal exon 5N, reducing the expression of this exon relative to the adult exon 5A. Two antiepileptic drugs, carbamazepine and phenytoin, act by binding to the alpha-subunit of neuronal sodium channels encoded by SCN1A. Among 425 and 281 epileptic patients treated with carbamazepine and phenytoin, respectively, Tate et al. (2005) found a significant association with the rs3812718 polymorphism and maximum dose needed to control symptoms; those with the G allele (and the neonatal SCN1A isoform) needed less medication. Maximum doses of carbamazepine averaged 1,313, 1,225, and 1,083 mg for AA, AG, and GG individuals, respectively; maximum doses of phenytoin averaged 373, 340, and 326 mg, for AA, AG, and GG individuals, respectively, suggesting a trend of reduction in maximum dose required according to genotype.
Heinzen et al. (2007) found that individuals with the G allele of rs3812718 had significantly increased levels of SCN1A transcripts containing exon 5N, consistent with the neonatal isoform, compared to those with the A allele. In addition, the G allele exhibited a dominant effect. These results were confirmed in a minigene expression system. Further studies in the minigene expression system suggested a role for NOVA2 (601991) in the regulation of splicing, with higher NOVA2 expression increasing the proportion of the neonate isoform including exon 5N; this effect was seen particularly with the AA genotype. Heinzen et al. (2007) noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets.
Petrovski et al. (2009) was unable to replicate the association between rs3812718 and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures.
In an analysis of 14 GEFS+ and 60 SMEI SCN1A missense mutations previously reported, Kanai et al. (2004) found that mutations in SMEI occurred more frequently in the 'pore' regions of SCN1A than did those in GEFS+. The SMEI pore region mutations were more strongly associated with the presence of ataxia and slightly earlier onset compared to mutations in other regions of the gene. Although the genotype-phenotype correlation was statistically significant, SMEI mutations also occurred outside the pore region and GEFS+ mutations occurred inside the pore region. Three SCN1A mutations were identified in both groups.
Mulley et al. (2005) found that the more than 100 epilepsy-associated mutations reported in the SCN1A gene to that time were spread throughout the gene. Some clustering of mutations was observed in the C terminus and the loops between segments 5 and 6 of the first 3 domains of the protein.
Kanai et al. (2009) performed a metaanalysis of the physiochemical effects of amino acid substitutions resulting from missense mutations in the SCN1A gene and their phenotypes in order to assess genotype/phenotype correlations. From 33 articles, they studied 155 missense mutations, including 22 associated with GEFS+, 14 associated with an intermediate phenotype (e.g., T1709I; 182389.0013), and 119 associated with a severe phenotype, including SMEI. Changes that resulted in decreased hydrophobicity in the S1-S4 transmembrane region outside of the pore region were significantly associated with a more severe phenotype. These changes may affect the stability of the transmembrane domains, which lie within the hydrophobic lipid layer. In addition, mutations that resulted in large changes in the isoelectric point within the pore region were associated with a more severe phenotype. Changes in charge on the surface of the pore may affect the function of the pore of the ion channel. However, patch-clamp studies were unable to find significant associations between changes in physicochemical properties and functional characteristics of mutated channels.
By polymerase chain reaction (PCR), Blanchard and Ingram (1991) isolated the SCN1A gene from a library of EcoRI fragments from flow-sorted chromosome 21. Primers were selected from a highly conserved region in the rat brain sodium channel I-alpha cDNA sequence. The assignment to chromosome 21 was subsequently found to be an error, presumably due to contamination of the chromosome 21 library by material from chromosome 2 (Malo, 1993).
Yu et al. (2006) found that Scn1a -/- mice developed severe ataxia and seizures and died on postnatal day 15. Scn1a +/- mice had spontaneous seizures and sporadic deaths beginning after postnatal day 21, with a notable dependence on genetic background. Loss of Scn1a did not change voltage-dependent activation or inactivation of sodium channels in hippocampal neurons. However, the sodium current density was substantially reduced in inhibitory interneurons of Scn1a -/- and +/- mice. The findings suggested that reduced sodium currents in GABAergic inhibitory interneurons resulting from heterozygous SCN1A mutations may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
Ogiwara et al. (2007) generated a knockin mouse line with a loss-of-function mutation in the Scn1a gene. Both homozygous and heterozygous mutant mice developed seizures within the first postnatal month. Homozygous mice also showed gait instability, and both groups showed early death. Immunohistochemical studies on wildtype mice showed relatively intense Scn1a expression in caudal brain parts, including the thalamus, superior colliculus, inferior colliculus, pons, medulla, deep cerebellar nuclei, and spinal cord, with lower expression in the hippocampus, cerebral cortex, and cerebellum. In the developing neocortex, Scn1a expression was clustered predominantly in axon initial segments of parvalbumin-positive interneurons and in nodes of Ranvier in the cerebellar white matter. Pyramidal neurons in the hippocampus showed low levels of Scn1a. Scn1a expression was absent in homozygous knockin mutant mice. In heterozygous mice, trains of evoked action potentials in fast-spiking inhibitory cells showed pronounced spike amplitude decrements late in the burst, suggesting that Scn1a is necessary to maintain but not initiate fast spiking. Ogiwara et al. (2007) concluded that haploinsufficiency of the Scn1a gene underlies seizures.
Martin et al. (2007) showed that the seizure severity of heterozygous Scn1a +/- mice (see Yu et al., 2006), which is a mouse model for SMEI, was ameliorated by a heterozygous point mutation (med-jo) in the Scn8a gene (600702). Double-heterozygous Scn1a +/- and Scn8a +/(med-jo) mice had seizure thresholds that were comparable to wildtype littermates, and the Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a +/- mice and extended the life span of Scn1a -/- mice. The authors hypothesized that the opposing effects of Scn1a and Scn8a dysfunction on seizure thresholds result from differences in the cell types that are influenced by the respective sodium channel subtypes. Scn1a mutants result in reduced sodium currents in inhibitory GABAergic interneurons of the hippocampus and cortex, whereas Scn8a mutants affect excitatory pyramidal cells of the hippocampus and cortex, suggesting that reduced excitability of these cells may underlie the elevated seizure resistance of Scn8a-mutant mice. Martin et al. (2007) suggested that their results demonstrated that genetic interactions can alter seizure severity, and supported the hypothesis that genetic modifiers, including the SCN8A gene, contribute to the clinical variability observed in SMEI and GEFS+.
Oakley et al. (2009) generated a mouse model of SMEI by targeted heterozygous deletion of the Scn1a gene. Mutant mice developed seizures induced by elevated core body temperature, whereas wildtype mice were unaffected. In 3 age groups studied, none of postnatal day (P) 17 to 18 mutant mice had temperature-induced seizures, but nearly all P20 to P22 and P30 to P46 mutant mice developed myoclonic seizures followed by generalized seizures caused by elevated core body temperature. There was an age-related susceptibility to seizures at lower temperatures as well as a general increase in severity of seizures with increasing age. Spontaneous seizures were only observed in mice older than P32, suggesting that mutant mice become susceptible to temperature-induced seizures before spontaneous seizures. Interictal EEG spike activity was seen at normal body temperature in most P30 to P46 mutant mice, but not in P20 to P22 or P17 to P18 mutant mice, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20 to P22 mutant mice had interictal spike activity with elevated body temperature. Oakley et al. (2009) concluded that their results defined a critical developmental transition for susceptibility to seizures in SMEI, demonstrated that body temperature elevation alone is sufficient to induce seizures in mutation carriers, and revealed a close correspondence between human and mouse SMEI in the temperature and age dependence of seizure frequency and severity.
Han et al. (2012) reported that mice with Scn1a haploinsufficiency exhibit hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a +/- mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of Na(v)1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABA(A) receptors, completely rescued the abnormal social behaviors and deficits in fear memory in the mouse model of Dravet syndrome (607208), demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. Han et al. (2012) concluded that their results demonstrated a critical role for Na(v)1.1 channels in neuropsychiatric functions and provided a potential therapeutic strategy for cognitive deficit and autism spectrum behaviors in Dravet syndrome.
Stein et al. (2019) found that hippocampus-specific deletion of Scn1a in mice resulted in selective reduction in excitability of inhibitory neurons. It also induced thermally evoked seizures, as well as spatial learning and memory defects, as seen in mice with global deletion of Scn1a. However, unlike global deletion of Scn1a, hippocampal deletion of Scn1a did not cause hyperactivity or defects in cognitive abilities, social interaction, and context-dependent fear conditioning.
In a 3-generation pedigree segregating autosomal dominant generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403) previously reported by Baulac et al. (1999), Escayg et al. (2000) identified a G-to-A transition at nucleotide 4943 in exon 26 of the SCN1A gene that resulted in an amino acid substitution, arg1648 to his. This mutation causes loss of the MaeII site and cosegregated with GEFS+2 in this family. The mutation was identified in 1 asymptomatic individual and was interpreted as an example of incomplete penetrance. One seemingly affected individual did not carry the mutation, suggesting it as a phenocopy; this was previously suggested by haplotype reconstruction.
In a family previously reported by Moulard et al. (1999) with GEFS+2 (GEFSP2; 604403), Escayg et al. (2000) identified a C-to-T transition at nucleotide 2624 of the SCN1A gene, resulting in an amino acid substitution thr875 to met. This mutation results from the loss of an Acl1 site. Eleven affected individuals and an obligate carrier were heterozygous for the mutation, whereas 4 unaffected relatives carried 2 normal alleles.
In affected members of a large multigenerational Australian family (family A) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) identified a heterozygous c.563A-T transversion in exon 4 of the SCN1A gene, resulting in an asp188-to-val (D188V) substitution at a conserved residue. The family had previously been reported by Scheffer and Berkovic (1997). Functional studies of the variant and studies of patient cells were not performed.
In affected members of an Ashkenazi Jewish family (family B) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) used single-strand conformation analysis (SSCA) to identify a heterozygous c.4057G-C transversion in exon 21 of the SCN1A gene, resulting in a val1353-to-leu (V1353L) substitution at a highly conserved residue in the S5 segment of domain III. Functional studies of the variant and studies of patient cells were not performed.
In affected members of a Druze family (family C) with GEFS+2 (GEFSP2; 604403), Wallace et al. (2001) identified a heterozygous c.4968C-G transversion in the SCN1A gene, resulting in an ile1656-to-met (I1656M) substitution in the S4 segment of domain IV. Functional studies of the variant and studies of patient cells were not performed.
Escayg et al. (2001) identified a T-to-C transition in exon 18 of the SCN1A gene, resulting in a trp1204-to-arg (W1204R) missense mutation, as the cause of GEFS+2 (GEFSP2; 604403).
In a 4-year-old boy (EP153) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous 2-bp deletion (c.657_658delAG) in exon 5 of the SCN1A gene, predicted to result in a frameshift and premature termination (Ser219fsTer275). Functional studies of the variant and studies of patient cells were not performed. The patient presented with seizures at 3 months of age; he died at 4 years of age.
In a 6-year-old boy (EP78) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous c.664C-T transition in exon 5 of the SCN1A gene, resulting in an arg222-to-ter (R222X) substitution. Functional studies of the variant and studies of patient cells were not performed. The patient developed seizures at 6 months of age.
In a 2-year-old girl (EP147) with Dravet syndrome (DRVT; 607208), Claes et al. (2001) identified a de novo heterozygous c.2956C-T transition in exon 16 of the SCN1A gene, resulting in a leu986-to-phe (L986F) substitution in the S6 region of domain II. Functional studies of the variant and studies of patient cells were not performed. She had onset of seizures at 4 months of age.
In a large family in which 27 members (18 still living) had febrile seizures accompanied in some by partial as well as generalized seizures (GEFSP2; 604403), Abou-Khalil et al. (2001) identified an A-to-C transversion at nucleotide 3809 of the SCN1A gene, resulting in a lys1270-to-thr (K1270T) substitution, in all affected members. The mutation was also present in 1 asymptomatic member, which was explained by the authors as incomplete penetrance. Pedigree analysis revealed autosomal dominant transmission.
In a Japanese patient with GEFS+2 (GEFSP2; 604403) associated with the development of partial epilepsy, Sugawara et al. (2001) identified a 4283T-C missense mutation in the SCN1A gene, resulting in a val1428-to-ala substitution. The mutation occurred in the pore-forming region of the sodium channel, which the authors hypothesized may affect ion selectivity.
In affected members of 3 European families with familial hemiplegic migraine-3 (609634), Dichgans et al. (2005) identified a heterozygous 4465C-A transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-lys (Q1489K) substitution in the cytoplasmic linker between domains III and IV, which is critical for fast inactivation. The mutation occurs in a highly conserved residue of the protein and was not identified in 1400 control chromosomes. Functional expression studies showed that the Q1489K substitution resulted in a 2- to 4-fold faster recovery from fast inactivation. The mutation was predicted to allow higher neuronal firing rates and enhanced excitability. Dichgans et al. (2005) suggested that the mutation may facilitate initiation and propagation of cortical spreading depression, which is thought to be related to migraine aura.
In a patient with Dravet syndrome (DRVT; 607208), Fujiwara et al. (2003) identified a heterozygous c.5126C-T transition in the SCN1A gene, resulting in a thr1709-to-ile (T1709I) substitution in domain IV of the protein. The patient's mother, who also carried the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; 604403). The T1709I substitution was not identified in 109 control chromosomes.
In a patient with a Dravet syndrome (DRVT; 607208), Fujiwara et al. (2003) identified a heterozygous c.4831G-T transversion in the SCN1A gene, resulting in a val1611-to-phe (V1611F) substitution in domain IV of the protein. The patient's mother, who also had the mutation, had a history of febrile seizures consistent with GEFS+ (GEFSP2; 604403). The V1611F substitution was not identified in 93 control chromosomes.
In 12 affected members of an Italian family with simple febrile seizures-3 (FEB3A; see 604403), Mantegazza et al. (2005) identified a heterozygous 434T-C transition in exon 3 of the SCN1A gene, resulting in a met145-to-thr (M145T) substitution of a highly conserved residue in the first transmembrane segment (S1) of domain I. The mutation was not identified in unaffected family members or in 50 control individuals. Functional expression studies showed that the M145T mutation resulted in a 60% reduction of current density and a 10-mV positive shift of the activation curve. Mantegazza et al. (2005) considered the findings consistent with a loss-of-function mutation. Three affected individuals later developed mesial temporal lobe epilepsy, 2 of whom had associated mesial temporal sclerosis on MRI.
In a 2-stage case-control study including a total of 234 patients with febrile seizures (FEB3A; see 604403), Schlachter et al. (2009) found a significant association between the major A allele of rs3812718 and febrile seizures (first stage p value of 0.000017; replication p value of 0.00069). The data suggested that homozygosity for the A allele confers a 3-fold increased relative risk of febrile seizures and may account for a population attributable risk factor of up to 50%. The data were consistent with the hypothesis that low-risk variants with a high population frequency contribute to the risk of common and genetically complex diseases such as epilepsy.
The SCN1A IVS5N+5G-A polymorphism, formerly SCN1A IVS5-91G-A (rs3812718), was shown by Tate et al. (2005) to affect the alternative splicing of exon 5. The major allele, A, disrupts the consensus sequence of fetal exon 5N, resulting in decreased expression of the fetal SCN1A isoform compared to the adult isoform. Among a total of 706 patients with epilepsy, Tate et al. (2005) found maximum required antiepileptic drug dose to be lowest in patients with a GG genotype, intermediate in those with the GA genotype, and highest in those with the AA genotype. Tate et al. (2005) emphasized that their findings required replication. In a separate study by Tate et al. (2006) that involved patients of Chinese ancestry, an association was found between SCN1A IVS5N+5G-A and phenytoin serum concentrations at maintenance dose; presence of the A allele was associated with higher doses.
Heinzen et al. (2007) found that in human brain tissue, the SCN1A IVS5N+5G-A polymorphism has a substantial effect on the percentage of transcripts containing exon 5N (neonatal form) of SCN1A. Individuals with the AA genotype had a mean of 0.7% of SCN1A transcripts in the neonatal form, whereas subjects with the GG genotype had 41% of transcripts containing exon 5N. The G allele elicited a dominant effect, with those with the AG genotype having 28% of transcripts in the neonatal form. Heinzen et al. (2007) noted that individuals with the AA genotype require increased doses of antiepileptic drugs compared to those with the GG genotype, suggesting that patients with the AA genotype have a more severe form of epilepsy. Alternatively, the different splice forms may cause alterations in pharmacology, since the drugs act on the SCN1A gene. The authors noted that future work was required to elucidate the functional differences between the transcripts containing exons 5A and 5N. The findings emphasized an emerging role of genetic polymorphisms in modulation of drug effect, and illustrated the importance of considering the activity of compounds at alternative splice forms of drug targets.
Petrovski et al. (2009) was unable to replicate the association between rs3812718 and febrile seizures in a study of 558 Australian patients with seizures, including 76 (14%) with febrile seizures and 482 (86%) without febrile seizures. Only 10 (2%) had isolated febrile seizures. The association was also not replicated in a second cohort of 1,589 European patients with focal epilepsy, consisting of 232 with febrile seizures and 1,357 without febrile seizures.
Buoni et al. (2006) identified a de novo heterozygous 1-bp deletion (c.2528delG) in exon 14 of the SCN1A gene in a 13-year-old boy with generalized epilepsy with febrile seizures plus, type 2 (GEFSP2; 604403). The mutation was predicted to result in a frameshift and premature termination of the protein at codon 853. The patient had prolonged febrile seizures at ages 6, 10, and 13 months, afebrile complex partial seizures with secondary generalization beginning at age 18 months, and 2 episodes of status epilepticus at age 2 years. He also had abnormal EEG findings and myoclonic jerks. Antiepileptic medication was unsuccessful. At age 4 years, the seizure frequency decreased in response to medication, and by age 9, he had complex partial seizures with secondary generalization. By age 13, he was treated with valproate and had a febrile seizure. He did not have intellectual disability. Buoni et al. (2006) emphasized the relatively benign outcome in this patient despite a truncating mutation in the SCN1A gene.
In a patient with Dravet syndrome (DRVT; 607208) manifest as severe myoclonic epilepsy of infancy (SMEI), Mulley et al. (2006) used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exons 21 through 26 of the SCN1A gene. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations.
In a patient with Dravet syndrome (DRVT; 607208) manifest as severe myoclonic epilepsy of infancy (SMEI), Mulley et al. (2006) used multiplex ligation-dependent probe amplification (MLPA) to identify a de novo heterozygous deletion of exon 21 of the SCN1A gene. Sequence analysis showed that the deletion was 6,499 bp in size and encompassed part of intron 20, all of exon 21, and part of intron 21. The phenotype was similar to SMEI patients with coding or splicing SCN1A mutations.
In a female patient with Dravet syndrome (DRVT; 607208), McArdle et al. (2008) identified a heterozygous 1-bp deletion (c.3608delA) in the SCN1A gene, predicted to result in a frameshift and premature termination in the intracellular cytoplasmic linker region between domains D2 and D3. She died at age 5 years. Postmortem Western blot analysis of cerebellar tissue did not detect the truncated protein but only the full-length protein. However, RT-PCR analysis found expression of both alleles in cerebellar tissue from the patient, with slightly greater expression of the wildtype transcript. The findings indicated that nonsense-mediated mRNA decay could not explain the lack of mutant protein expression. McArdle et al. (2008) speculated that the mutant truncated protein may have been misfolded in the endoplasmic reticulum and then been targeted for ER-associated protein degradation, suggesting haploinsufficiency as the disease mechanism.
In affected members of a 3-generation French family with familial hemiplegic migraine (FHM3; 609634), Vahedi et al. (2009) identified a heterozygous 4495T-C transition in exon 24 of the SCN1A gene, resulting in a phe1499-to-leu (F1499L) substitution in a highly conserved residue in an intracellular loop. The proband was an 18-year-old woman who also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes; her affected mother, sister, and maternal grandfather did not have episodic blindness. Vahedi et al. (2009) noted that ERDB has features of spreading depression in the retina, with propagation of the darkness from the periphery to the center and a refractory period.
In 4 affected members of a Swiss family with familial hemiplegic migraine (FHM3; 609634), previously reported by Le Fort et al. (2004), Vahedi et al. (2009) identified a heterozygous 4467G-C transversion in exon 23 of the SCN1A gene, resulting in a gln1489-to-his (Q1489H) substitution in a highly conserved residue in an intracellular loop. All 4 affected family members also had episodes of elicited repetitive daily blindness (ERDB) that was temporally unrelated to the FHM episodes. Vahedi et al. (2009) noted that ERDB has features of spreading depression, with propagation of the darkness from the periphery to the center and a refractory period. A different mutation in this same codon has also been associated with FHM3 (Q1489K; 182389.0012).
In a female infant with Dravet syndrome (DRVT; 607208) manifest clinically as 'malignant migrating partial seizures of infancy' (MPSI, MMPSI), Freilich et al. (2011) identified a heterozygous c.5006C-A transversion in the SCN1A gene, resulting in an ala1669-to-glu (A1669E) substitution in a highly conserved residue in a cytoplasmic linker region between transmembrane segments 4 and 5 of domain 4. The mutation was predicted to be deleterious; functional studies were not performed. RT-PCR studies of the patient's brain matter showed that the mutant transcript was expressed similar to wildtype (ratio of 40:60). The patient was born by in vitro fertilization from a donor ovum and paternal sperm; the father did not carry the mutation, and DNA was not available from the ovum donor. The patient had a severe phenotype, with onset of seizures at age 10 weeks, progression to refractory recurrent seizures by age 5 months, status epilepticus, EEG evidence of migrating focal onset progressing to multifocal onset of seizures, progressive microcephaly, and profound psychomotor delay. She died at age 9 months. The findings expanded the severity of the phenotype associated with SCN1A mutations.
In an 8-year-old girl with Dravet syndrome (DRVT; 607208) manifest clinically as 'malignant migrating partial seizures of infancy,' Carranza Rojo et al. (2011) identified a de novo heterozygous c.2584C-G transversion in exon 14 of the SCN1A gene, resulting in an arg862-to-gly (R862G) substitution in the voltage sensor segment S4 of the second protein domain. The mutation was predicted to be deleterious; functional studies were not performed. The patient had onset of multifocal hemiclonic seizures at age 2 weeks with episodes of status epilepticus. She had acquired microcephaly, developmental regression, and severe intellectual disability. The findings expanded the severity of the phenotype associated with SCN1A mutations.
In a 6-year-old Japanese girl with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Ohashi et al. (2014) identified a de novo heterozygous c.1264G-T transversion in the SCN1A gene, resulting in a val422-to-leu (V422L) substitution in the transmembrane region S6 of the D1 domain. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or in 408 in-house Japanese controls. Functional studies of the variant were not performed.
In 8 unrelated children with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.677C-T transition in exon 5 of the SCN1A gene, resulting in a thr226-to-met (T226M) substitution. The mutations were found by whole-exome or targeted sequencing. Functional studies of the variant were not performed, but the authors speculated a gain-of-function effect. The patients had onset of seizures between 6 and 12 weeks of age. Several patients had previously been reported, including patients 3 and 4 who had been reported by Dhamija et al. (2014).
Harkin et al. (2007) had identified a de novo heterozygous T226M mutation in the SCN1A gene in a 5-year-old patient (patient 78) with onset of seizures at 2 months of age. The patient had severely impaired intellectual development and increased muscle tone. Another patient (patient 61) also carried the mutation; the latter patient was noted to have severe myoclonic epilepsy of infancy-borderland (SMEB), but clinical details were limited. Functional studies of the variant were not performed.
In a 12-year-old boy (patient 9) with developmental and epileptic encephalopathy-6B (DEE6B; 619317), Sadleir et al. (2017) identified a de novo heterozygous c.4033C-T transition in the SCN1A gene, resulting in a pro1345-to-ser (P1345S) substitution. Functional studies of the variant were not performed. The patient had onset of epileptic spasms around 6 weeks of age.
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