Alternative titles; symbols
HGNC Approved Gene Symbol: SCN1B
Cytogenetic location: 19q13.11 Genomic coordinates (GRCh38): 19:35,030,470-35,040,449 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.11 | Atrial fibrillation, familial, 13 | 615377 | Autosomal dominant | 3 |
| Brugada syndrome 5 | 612838 | 3 | ||
| Cardiac conduction defect, nonspecific | 612838 | 3 | ||
| Developmental and epileptic encephalopathy 52 | 617350 | Autosomal recessive | 3 | |
| Generalized epilepsy with febrile seizures plus, type 1 | 604233 | Autosomal dominant | 3 |
The SCN1B gene encodes a beta-1 subunit of voltage-gated sodium channels. Voltage-gated sodium channels are multimeric protein complexes essential for action potential generation in excitable cells, including neurons, and consist of a central pore-forming alpha-subunit and 2 beta-subunits. Sodium channel beta-1 subunits modulate channel voltage-dependence and gating, cell surface expression of the channel, and cell-cell and cell-matrix adhesion (summary by Patino et al., 2009).
By PCR of human brain RNA using sequences from rat Scn1b, followed by screening a human frontal cortex cDNA library, McClatchey et al. (1993) cloned SCN1B. The C-terminal half of the deduced 218-amino acid protein contains a transmembrane domain. Rat and human SCN1B share 98% amino acid identity. Northern blot analysis detected abundant expression of a 1.5-kb transcript in several human brain regions, including brainstem and cerebellum. Expression was also detected in human skeletal muscle and heart and in rat myoblasts, but not in human liver.
By in situ hybridization of rat brain, Morgan et al. (2000) detected highest expression of Scn1b in cerebellum and hippocampus. In most areas, expression of Scn1b complemented the expression of Scn3b (608214). The exception was hippocampus, where both subunits were expressed at high levels.
Qin et al. (2003) identified a splice variant of SCN1B that they designated beta-1B. The deduced 268-amino acid beta-1B protein has a calculated molecular mass of 30.4 kD. The N-terminal 149 amino acids are identical between beta-1B and the previously identified 218-amino acid beta-1 subunit, but their C-terminal sequences share only 17% amino acid identity. Northern blot analysis detected high expression of a 7.5-kb beta-1B transcript in brain and skeletal muscle, and much lower levels in heart, placenta, lung, liver, kidney, and pancreas. Within specific brain regions, expression was highest in cerebellum, followed by cerebral cortex and occipital lobe. Skeletal muscle expressed a second transcript of about 1.5 kb. Immunohistochemical analysis detected beta-1B in many regions of the human brain, including cerebellar Purkinje cells, cortical pyramidal neurons, and neuronal fibers throughout the brain. Strong labeling was detected in human dorsal root ganglion, spinal nerve fibers, and cortical neurons and their processes.
Watanabe et al. (2008) performed quantitative real-time PCR in nondiseased human heart and detected beta-1 and beta-1B transcripts in the right and left ventricles, with even higher transcript levels of both in the Purkinje (conduction) fibers: 1.6- and 2.4-fold higher for beta-1, and 3.7- and 4.8-fold higher for beta-1B, compared to the right and left ventricles, respectively.
In nondiseased human heart tissue, Watanabe et al. (2009) observed expression of SCN1B transcript in both atrium and ventricle, with greater abundance in the ventricle.
By quantitative PCR analysis, Olesen et al. (2011) demonstrated expression of SCN1B in human atria and ventricles.
By screening rodent-human hybrid cell lines, McClatchey et al. (1993) mapped the SCN1B gene to chromosome 19. Using a 15.9-kb genomic SCN1B clone, Makita et al. (1994) assigned the gene to 19q13.1-q13.2 by fluorescence in situ hybridization. They found an intragenic polymorphic (TTA)n repeat positioned between 2 tandem Alu repetitive sequences. Makita et al. (1994) suggested that this polymorphism could be useful in evaluating SCN1B as a candidate gene for hereditary disorders affecting membrane excitability. Three voltage-gated potassium channels had been mapped to chromosome 19: KCNA7 (176268), KCNC2 (176256), and KCNC3 (176264).
Makita et al. (1994) analyzed the structure of the SCN1B gene. A complete coding region was found in approximately 9.0 kb of genomic DNA and comprised 5 exons, ranging in size from 72 to 749 bp, and 4 introns, ranging in size from 90 bp to 5.5 kb.
Qin et al. (2003) determined that the SCN1B gene contains 6 alternatively spliced exons and spans about 9 kb.
McClatchey et al. (1993) found that coexpression of the human beta-1 subunit and the rat muscle alpha subunit (SCN4A; 603967) in Xenopus oocytes accelerated the inactivation of the sodium current 5-fold and shifted the point of half-maximal inactivation 10 mV in the hyperpolarizing direction compared with oocytes expressing the alpha subunit alone. The rate of the voltage dependence of inactivation was not affected. Beta-1 increased the peak amplitude of the sodium current an average of 2-fold, but the variability was quite large.
Tammaro et al. (2002) expressed the rat beta-1 subunit in human embryonic kidney cells stably expressing the rat alpha subunit (SCN4A). They found that beta-1 increased the density of sodium channels on the cell surface and modulated the inactivation of the sodium current, hastening recovery from inactivation.
By functional expression of rat Scn3b or Scn1b with rat Scn2a1 (182390) in Xenopus oocytes, Morgan et al. (2000) determined that both Scn3b and Scn1b caused a hyperpolarizing shift in the voltage-dependence of inactivation and modulated the alpha subunit by increasing the fraction of channels operating in the fast-gating mode. The kinetics were distinct, with Scn1b inactivating channel opening more quickly than Scn3b.
Qin et al. (2003) found that coexpression of the human beta-1B variant with Nav1.2 (SCN2A; 182390) in Xenopus oocytes increased the ionic current over that obtained with Nav1.2 alone. There were no significant changes in voltage-dependent kinetics or steady-state properties of the channel.
Generalized Epilepsy With Febrile Seizures Plus, Type 1
In affected members of a large multigenerational family from Tasmania with generalized epilepsy with febrile seizures plus-1 (GEFSP1; 604233) reported by Singh et al. (1999), Wallace et al. (1998) identified a heterozygous missense mutation in the SCN1B gene (C121W; 600235.0001). The mutation segregated with the disorder in the family, although there was phenotypic variability.
Grinton et al. (2022) examined 14 unrelated families from Australia, the United Kingdom, and the United States with GEFS+, all with the same heterozygous mutation in the SCN1B gene (C121W; 600235.0001). The authors identified a core ancestral haplotype spanning about 260 kb that was shared by all 14 families. The age of the most recent common ancestor of these families was estimated at 31.2 generations or about 800 years earlier. The penetrance of this variant in these multigenerational families was about 70%. Analysis of UK Biobank whole-exome sequencing data identified the heterozygous variant in 74 (0.039%) unrelated persons. Most of these carriers (89%) shared the full core ancestral haplotype, while the others shared smaller regions of the core haplotype. All 74 shared segments of the extended haplotype outside the core haplotype region. The variant was seen 14 times more often in the European cohort of the UK Biobank than in the gnomAD database, supporting the variant being of British origin. The authors concluded that variants that are present in the population at low frequencies should be considered as potentially pathogenic when the phenotype is mild and incompletely penetrant.
Brugada Syndrome 5 and Cardiac Conduction Defects
Watanabe et al. (2008) analyzed the SCN1B gene in 282 probands with Brugada syndrome and 44 patients with conduction disease (see BRGDA5, 612838), all of whom were negative for mutation in the SCN5A gene, and identified 3 mutations in 3 kindreds, 1 French, 1 Turkish, and 1 Dutch (600235.0003, 600235.0004, and 600235.0005, respectively), that segregated with disease and were not found in 1,404 population controls. None of the mutation-positive families had a history of epilepsy. Two of the mutations were located in the alternately processed beta-1B transcript; functional studies demonstrated a lower sodium current when Na(v)1.5 was coexpressed with mutant beta-1 or beta-1B subunits than with wildtype.
Familial Atrial Fibrillation 13
Watanabe et al. (2009) screened the 4 genes encoding sodium channel beta subunits, SCN1B, SCN2B (601327), SCN3B (608214), and SCN4B (608256), in 480 patients with atrial fibrillation (AF), including 118 patients with lone AF and 362 patients with AF and other cardiovascular disease. They identified 2 unrelated female patients, 1 with AF and aortic stenosis and 1 with lone AF (ATFB13; 615377), who had heterozygous missense mutations in the SCN1B gene, R85H (600235.0006) and D153N (600235.0007), respectively. Sequencing of the SCN5A gene in the 2 women revealed no mutations, and the SCN1B variants were not found in a total of 638 controls. Another 2 AF patients were found to have mutations in the SCN2B gene (601327.0001 and 601327.0002; see ATFB14, 615378), but no disease-causing variants were identified in SCN3B or SCN4B.
Developmental and Epileptic Encephalopathy 52
In a male infant, born of consanguineous Moroccan parents, with developmental and epileptic encephalopathy-52 (DEE52; 617350), Patino et al. (2009) identified a homozygous missense mutation in the SCN1B gene (R125C; 600235.0008). In vitro functional cellular expression studies showed that the mutant protein was poorly expressed at the cell surface, despite robust intracellular expression, consistent with a trafficking defect to the membrane. The inefficient trafficking of the mutant protein to the cell membrane at physiologic temperatures resulted in a functionally null SCN1B phenotype. The parents, who were heterozygous for the mutation, did not have seizures, suggesting that one functional SCN1B allele is sufficient for normal control of electrical excitability.
In a 25-year-old Japanese man with DEE52, who was born of unrelated parents, Ogiwara et al. (2012) identified a homozygous missense mutation in the SCN1B gene (I106F; 600235.0009). Functional studies of the variant and studies of patient cells were not performed. However, Ogiwara et al. (2012) noted that the domain of the protein affected by the mutation mediates interaction with cellular adhesion molecules. The patient was part of a cohort of 67 individuals with early-onset seizures without mutations in the SCN1A (182389) or SCN2A (182390) genes who underwent mutation analysis of the SCN1B gene.
Kim et al. (2013) did not find any pathogenic mutations in the SCN1B gene among 54 patients with early-infantile epileptic encephalopathy in whom SCN1A mutations had been excluded, suggesting that SCN1B mutations are not a common cause of that phenotype.
In affected members of 3 unrelated Saudi families with DEE52, Ramadan et al. (2017) identified homozygous mutations in the SCN1B gene: the same splicing mutation (600235.0010) in 2 families, and a missense mutation (Y119D; 600235.0011) in the third family. The mutations, which were found by sequencing of a multigene epilepsy panel and confirmed by Sanger sequencing, segregated with the disorder in the families and were not found in the ExAC database. No functional studies were performed.
Chen et al. (2004) produced beta-1-null mice by gene targeting. Knockout mice exhibited ataxic gait, spontaneous seizures, growth retardation, and death around postnatal day 20. They showed slowing of action potential conduction, reduced number of mature nodes of Ranvier, alterations in nodal architecture, loss of sodium channel-contactin (see CNTN1; 600016) interactions, and abnormalities in the expression of Nav1.1 (SCN1A; 182389) and Nav1.3 (SCN3A; 182391) in pyramidal neurons CA2/CA3. Mutant mice had impacted esophagi, possibly attributable to enteric nervous system impairment. Chen et al. (2004) concluded that beta-1 regulates sodium channel density and localization, is involved in axo-glial communication at nodes of Ranvier, and is required for normal action potential conduction and control of excitability in vivo.
Patino et al. (2009) found that heterozygous Scn1b +/- mice did not have increased susceptibility to seizures. Electrophysiologic studies of hippocampal slices from Scn1b-null mice showed increased peak voltage of action potentials and amplitude of action potentials in CA3 neurons, consistent with neuronal hyperexcitability, but not in CA1 neurons. Changes in sodium current density were not observed in dissociated CA3 bipolar neurons.
In affected members of a large family, most of them living in the Australian state of Tasmania (Singh et al., 1999), with generalized epilepsy with febrile seizures plus-1 (GEFSP1; 604233), Wallace et al. (1998) identified a heterozygous c.387C-G transversion in the SCN11B gene, resulting in a cys121-to-trp (C121W) substitution. The substitution occurred at a conserved residue in the putative disulfide bridge that normally maintains an extracellular immunoglobulin-like fold. Coexpression of mutant beta-1 subunit with a brain sodium channel alpha subunit in Xenopus laevis oocytes demonstrated that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele.
Tammaro et al. (2002) expressed wildtype rat beta-1 or mutant rat beta-1 with the C121W substitution in human embryonic kidney cells stably expressing the rat alpha subunit (SCN4A; 603967). Wildtype beta-1 increased the density of sodium channels on the cell surface and modulated the inactivation of the sodium current, hastening recovery from inactivation. In contrast, beta-1 with C121W lacked the ability to modulate sodium currents, but it maintained the ability to increase current density.
Wallace et al. (2002) identified a second family, from Queensland, Australia, with GEFS+ and the C121W mutation. Of 19 individuals with seizures, 16 had phenotypes within the GEFS+ spectrum. The mutation was present in 13 of 14 individuals with GEFS+ available for testing and in 1 of the 3 individuals with seizures not consistent with the GEFS+ phenotype. Four unaffected members tested also carried the mutation. The penetrance of the mutation in this family was determined to be 76%. A common haplotype was observed in this family and the family reported by Wallace et al. (1998), suggesting a founder effect.
Grinton et al. (2022) reported evidence of a single founder event giving rise to this variant in 14 unrelated families with the GEFS+ phenotype, which occurred about 800 years earlier. Grinton et al. (2022) stated that the nucleotide change in this variant is c.363C-G.
In affected members of a family with generalized epilepsy with febrile seizures plus (GEFSP1; 604233) inherited in an autosomal dominant pattern with reduced penetrance, Audenaert et al. (2003) identified a heterozygous A-to-C transversion in the splice acceptor site of exon 3 of the SCN1B gene, resulting in deletion of 5 amino acids within the extracellular immunoglobulin-like fold of the protein. The proband presented at age 17 months with frequent absence seizures that were not provoked by fever. Four other family members with the mutation had febrile seizures or febrile seizures plus. Three members who carried the mutation did not have seizures. Audenaert et al. (2003) noted the unusual phenotype of the proband with absence seizures.
In a 53-year-old French man who presented with chest pain but had normal coronary angiography and echocardiography, in whom electrocardiogram (ECG) revealed ST segment elevation typical of Brugada syndrome (BRGDA5; 612838), Watanabe et al. (2008) identified heterozygosity for a 536G-A transition in exon 3A of the SCN1B gene, resulting in a trp179-to-ter (W179X) substitution predicted to generate a truncated protein lacking the membrane-spanning segment and intracellular portion. The proband also had conduction abnormalities, including a prolonged PR interval of 220 ms and left anterior hemiblock, and ventricular fibrillation was induced by programmed electrical stimulation in the absence of drugs. The mutation was also found in the proband's brother, who had no history of palpitations or syncope, but on baseline ECG had left anterior hemiblock and minor ST segment elevation suggestive of Brugada syndrome (type II saddleback abnormalities); on flecainide challenge, the ST segment elevation was exacerbated but did not meet the criteria for a diagnostic (type I) pattern. Their sister, who also carried the mutation, had a normal ECG and a negative flecainide test, but her mutation-positive son was found to have right bundle branch block and type II Brugada syndrome after flecainide challenge. There was no family history of tachyarrhythmias, syncope, sudden cardiac death, or epilepsy. The mutation was not found in 1,404 population controls. Functional studies of the W179X mutation, which occurs only in the beta-1B transcript, showed that coexpression of wildtype beta-1B with Na(v)1.5 increased sodium current density by 69%, whereas coexpression with mutant beta-1B did not increase the sodium current compared to Na(v)1.5 alone; there was no evidence of a dominant-negative effect by the mutant. In addition, wildtype beta-1B produced negative shifts in the voltage dependence of Na(v)1.5 activation and inactivation, whereas mutant beta-1B did not modulate Na(v)1.5 gating.
In a 50-year-old Turkish woman who presented with palpitations and dizziness and had complete left bundle branch block on electrocardiogram (see 612838), Watanabe et al. (2008) identified heterozygosity for a 259G-C transversion in exon 3 of the SCN1B gene, resulting in a glu87-to-gln (E87Q) substitution at a highly conserved residue within the extracellular immunoglobulin loop. The proband had a prolonged His-ventricle interval of 80 ms and inducible atrioventricular nodal reentrant tachycardia; complete atrioventricular block occurred following atrial programmed stimulation and during induced tachycardia. The mutation was also identified in her brother, who had bifascicular block (right bundle branch block and left anterior hemiblock), and in their mother, who had a normal electrocardiogram. There was no family history of syncope, sudden cardiac death, or epilepsy. The mutation was not found in 1,404 population controls, including 150 unrelated Turkish individuals. Functional studies of the E87Q mutation, located in a region of the protein common to both the beta-1 and beta-1B transcripts, showed that coexpression of wildtype beta-1 or beta-1B with Na(v)1.5 significantly increased sodium current density (by 76% and 69%, respectively), whereas coexpression with mutant beta-1 or beta-1B did not increase the sodium current compared to Na(v)1.5 alone; coexpression of both wildtype and mutant beta-1 demonstrated a dominant-negative effect by the mutant. In addition, wildtype beta-1 or beta-1B produced negative shifts in the voltage dependence of Na(v)1.5 activation and inactivation, whereas mutant beta-1 or beta-1B shifted only the voltage dependence of inactivation.
In a 17-year-old Dutch girl who had right bundle branch block and a prolonged PR interval of 196 ms on electrocardiogram (see 612838), Watanabe et al. (2008) identified heterozygosity for a 537G-A transition in exon 3A of the SCN1B gene, resulting in a trp179-to-ter (W179X) substitution predicted to generate a truncated protein lacking the membrane-spanning segment and intracellular portion. The proband had a normal echocardiogram, and a flecainide test for Brugada syndrome was negative. The mutation was also found in her father, who had a normal electrocardiogram and a negative flecainide test. The family history was negative for syncope, sudden cardiac death, or epilepsy. The mutation was not found in 1,404 population controls. Functional studies of the W179X mutation, which occurs only in the beta-1B transcript, showed that coexpression of wildtype beta-1B with Na(v)1.5 increased sodium current density by 69%, whereas coexpression with mutant beta-1B did not increase the sodium current compared to Na(v)1.5 alone; there was no evidence of a dominant-negative effect by the mutant. In addition, wildtype beta-1B produced negative shifts in the voltage dependence of Na(v)1.5 activation and inactivation, whereas mutant beta-1B did not modulate Na(v)1.5 gating.
In a 68-year-old white woman with paroxysmal atrial fibrillation (ATFB13; 615377) and moderate aortic stenosis, Watanabe et al. (2009) identified heterozygosity for a c.254G-A transition in exon 3 of the SCN1B gene, resulting in an arg85-to-his (R85H) substitution at a highly conserved residue in the extracellular domain. Functional analysis in CHO cells demonstrated that there was no increase in peak sodium current amplitude when SCN5A (600163) was coexpressed with the R85H mutant, compared to a 75% increase with wildtype SCN1B. In addition, R85H resulted in a positive shift of voltage dependence of both activation and inactivation compared to wildtype; there was no difference in persistent sodium current with the mutant.
In a 57-year-old black woman with lone atrial fibrillation (ATFB13; 615377), Watanabe et al. (2009) identified heterozygosity for a c.457G-A transition in exon 4 of the SCN1B gene, resulting in an asp153-to-asn (D153N) substitution at a highly conserved residue in the extracellular domain. Functional analysis in CHO cells demonstrated that there was only a 24% increase in peak sodium current amplitude when SCN5A (600163) was coexpressed with the D153N mutant, compared to a 75% increase with wildtype SCN1B. However, D153N did not affect the voltage dependence of activation or inactivation, and there was no difference in persistent sodium current with the mutant compared to wildtype.
In a male infant, born of consanguineous Moroccan parents, with developmental and epileptic encephalopathy-52 (DEE52; 617350), who was clinically diagnosed with Dravet syndrome, Patino et al. (2009) identified a homozygous c.373C-T transition in exon 3 of the SCN1B gene, resulting in an arg125-to-cys (R125C) substitution at a conserved residue in the extracellular domain. The mutation segregated with the disorder in the family and was not found in 92 control individuals. Patch-clamp electrophysiologic studies in HEK293 and Chinese hamster lung 1610 fibroblasts transfected with the mutation showed that the mutant protein was poorly expressed at the cell surface, despite robust intracellular expression, consistent with a trafficking defect to the membrane. Studies in Xenopus oocytes showed that the mutant protein was functional if it could be expressed at the cell surface. The inefficient trafficking of the mutant protein to the cell membrane at physiologic temperatures resulted in a functionally null SCN1B phenotype. The parents, who were heterozygous for the mutation, did not have seizures, suggesting that 1 functional SCN1B allele is sufficient for normal control of electrical excitability. The patient had onset of refractory seizures at 3 months of age and died at around 14 months of age.
In a 25-year-old Japanese man, born of unrelated parents, with developmental and epileptic encephalopathy-52 (DEE52; 617350), who was clinically diagnosed with Dravet syndrome, Ogiwara et al. (2012) identified a homozygous c.316A-T transversion in exon 3 of the SCN1B gene, resulting in an ile106-to-phe (I106F) substitution at a highly conserved residue in the extracellular Ig loop domain. The unaffected parents were heterozygous for the mutation, which was not found in the dbSNP, Exome Variant Server, or 1000 Genomes Project databases, or in 312 control individuals. Functional studies of the variant and studies of patient cells were not performed. However, Ogiwara et al. (2012) noted that the domain of the protein affected by the mutation mediates interaction with cellular adhesion molecules. The patient had onset of seizures at about 6 months of age. He was part of a cohort of 67 individuals with early-onset seizures who underwent mutation analysis of the SCN1B gene.
In 2 affected sibs in each of 2 consanguineous Saudi families (families 1 and 3) with developmental and epileptic encephalopathy-52 (DEE52; 617350), Ramadan et al. (2017) identified homozygosity for a splice site mutation (c.449-2A-G, NM_001037.4) in intron 3 of the SCN1B gene. The mutation, which was identified by sequencing of a multigene epilepsy panel and confirmed by Sanger sequencing, segregated with the disorder in the families. The variant was not found in the ExAC database or in over 7,000 Saudi controls. No functional studies were performed. The patients had onset of seizures in the first months of life; all died in the first decade of life.
In a 10-year-old girl, born of consanguineous Saudi parents (family 2), with developmental and epileptic encephalopathy-52 (DEE52; 617350), Ramadan et al. (2017) identified homozygosity for a c.355T-G transversion (c.355T-G, NM_001037.4) in the SCN1B gene, resulting in a tyr119-to-asp (Y119D) substitution. The mutation, which was found by sequencing of a multigene epilepsy panel and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the ExAC database or in over 7,000 Saudi controls. No functional studies were performed. The patient had onset of seizures at 2 months of age and had almost no psychomotor development; a similarly affected sister died at age 8 years.
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