Alternative titles; symbols
HGNC Approved Gene Symbol: SCN2B
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38) : 11:118,162,806-118,176,639 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | Atrial fibrillation, familial, 14 | 615378 | Autosomal dominant | 3 |
The beta-2 subunit of the mammalian brain voltage-gated sodium channel is a 186-residue glycoprotein that contains an extracellular N-terminal domain with similarity to the neural adhesion molecule contactin (600016), as well as a single transmembrane domain (Isom et al., 1995).
By immunocytochemical analysis of mouse brain sections, Chen et al. (2002) found Scn2b in many regions of the nervous system, including the nodes of Ranvier of sciatic nerve and white matter tracts in the cerebellum, cell bodies of hippocampal and cortical pyramidal neurons, and cerebellar Purkinje neurons.
In nondiseased human heart tissue, Watanabe et al. (2009) observed expression of SCN2B transcript in both atrium and ventricle, with similar transcript levels in the 2 chambers.
Bolino et al. (1998) reported that the SCN2B gene contains 4 exons and spans approximately 12 kb.
By fluorescence in situ hybridization, Eubanks et al. (1997) mapped the SCN2B gene to 11q23. Bolino et al. (1998) confirmed the assignment of the SCN2B gene to chromosome 11q23.
Jones et al. (1996) used a rat brain Scn2b cDNA to map the mouse gene in interspecific backcrosses. They found that it is linked to markers from the central region of mouse chromosome 9 and noted that the neurologic mutation 'staggerer' (Imai and Kingsley, 1994) had been mapped there also. No recombination was found with the Il10r gene (146933). Thus, mouse Scn2b is located within a conserved linkage group with orthologs on human chromosome 11q22-qter.
The large alpha subunits of mammalian voltage-gated sodium channels (e.g., 182390) can generate a functional channel when expressed alone in Xenopus oocytes, but association with beta-1 (600235) or beta-2 subunits modifies channel function. Jones et al. (1996) stated that the beta-2 subunit is expressed in central neurons only, where covalent association with the alpha subunit is correlated with insertion into the cell membrane.
Using cell-based assays, Kim et al. (2007) showed that the voltage-gated sodium channel (Nav1) beta-2 subunit was sequentially cleaved by BACE1 (604252), which released the beta-2 C-terminal fragment, and by gamma-secretase (see PSEN1; 104311), which released the beta-2 intracellular domain. Expression of the isolated beta-2 intracellular domain increased the mRNA and protein levels of the Nav1.1 alpha subunit (SCN1A; 182389) in human and rodent neuroblastoma cells. Brains of BACE1-transgenic mice and Alzheimer disease (104300) patients with elevated BACE1 levels exhibited elevated levels of beta-2 C-terminal fragment and Nav1.1 protein. However, in both rodent neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice, Nav1.1 accumulated inside the cell rather than at the cell surface, and there was marked reduction in Nav1-mediated sodium current density. Kim et al. (2007) concluded that BACE1 regulates cell surface sodium current densities via beta-2 cleavage and may contribute to neurodegeneration.
Familial Atrial Fibrillation 14
Watanabe et al. (2009) screened the 4 genes encoding sodium channel beta subunits, SCN1B (600235), SCN2B, SCN3B (608214), and SCN4B (608256), in 480 patients with atrial fibrillation, including 118 patients with lone AF and 362 patients with AF and other cardiovascular disease. They identified 2 unrelated male patients, 1 with AF and hypertension and 1 with lone AF (ATFB14; 615378), who had heterozygous missense mutations in the SCN2B gene, R28W (601327.0001) and R28Q (601327.0002), respectively. Sequencing of the SCN5A gene (600163) in the 2 men revealed no mutations, and the SCN2B variants were not found in a total of 638 controls. Another 2 patients were found to have mutations in the SCN1B gene (600235.0006 and 600235.0007; see ATFB13, 615377), but no disease-causing mutations were identified in SCN3B or SCN4B.
Possible Association with Brugada Syndrome
See 601327.0003 for discussion of a possible association between variation in the SCN2B gene and Brugada syndrome (see 601144).
Chen et al. (2002) found that brain development in Scn2b-null mice was grossly normal. Knockout mice displayed increased susceptibility to seizures, but they seemed normal in other neurologic tests. Knockout mice had normal fiber number and sodium channel localization in myelinated axons, but there was reduced channel number as measured by the ability of mutant neurons to bind a sodium channel blocker. Electrophysiologically, loss of Scn2b resulted in negative shifts in the voltage dependence of inactivation and significantly decreased sodium current density in dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was reduced, and the threshold for action potential generation was increased, but there was no change in the conduction velocity. Chen et al. (2002) concluded that SCN2B-mediated regulation of sodium channel density and function in neurons is required for normal action potential generation and control of excitability.
In a 61-year-old white man with paroxysmal atrial fibrillation (ATFB14; 615378) and hypertension, Watanabe et al. (2009) identified heterozygosity for a c.82C-T transition in exon 2 of the SCN2B gene, resulting in an arg28-to-trp (R28W) substitution at a highly conserved residue in the extracellular domain. Functional analysis in CHO cells demonstrated a reduction of peak current by 30% at -30 mV with the R28W mutant compared to wildtype. In addition, R28W resulted in a positive shift of voltage dependence of activation compared to wildtype, but did not affect inactivation; there was no difference in persistent sodium current with the mutant.
In a 57-year-old white man with paroxysmal lone atrial fibrillation (ATFB14; 615378), Watanabe et al. (2009) identified heterozygosity for a c.83G-A transition in exon 2 of the SCN2B gene, resulting in an arg28-to-gln (R28Q) substitution at a highly conserved residue in the extracellular domain. Functional analysis in CHO cells demonstrated a reduction of peak current by 36% at -30 mV with the R28Q mutant compared to wildtype. In addition, R28Q resulted in a positive shift of voltage dependence of activation and inactivation compared to wildtype; there was no difference in persistent sodium current with the mutant.
This variant is classified as a variant of unknown significance because its contribution to Brugada syndrome (see 601144) has not been confirmed.
In a 47-year-old woman with Brugada syndrome, Riuro et al. (2013) identified heterozygosity for a c.632A-G transition in the SCN2B gene, resulting in an asp211-to-gly (D211G) substitution at a conserved residue within the intracellular C terminus. The proband, who had syncopal episodes from 12 years of age, was diagnosed with Brugada syndrome in her 30s after identification of ST elevation in the right precordial leads on electrocardiogram (ECG). Electrophysiologic study induced polymorphic ventricular tachycardia requiring cardioversion, and a cardioverter defibrillator was implanted. The mutation was also present in her 'presymptomatic' father and sister and in her asymptomatic brother. Her 74-year-old father had a history of palpitations and showed first-degree atrioventricular block but no ST segment elevation on ECG, and her 43-year-old sister had nondiagnostic ST elevation in leads V1 and V2 with incomplete right bundle branch block; her 40-year-old brother did not show any ST segment elevation on ECG. Flecainide testing was not performed in the family. Functional analysis in transfected CHO cells demonstrated a 39.4% reduction in sodium current density with the mutant compared to wildtype. Voltage dependence of activation and steady-state inactivation as well as recovery from inactivation and inactivation time constants were similar for the D211G mutant and wildtype SCN2B. However, biotin pull-down assays revealed lower voltage-gated sodium channel levels on the CHO cell surface with the mutant compared to wildtype. Riuro et al. (2013) concluded that the D211G mutation induces a reduction in I(Na) density, most likely by decreasing Na(v)1.5 cell surface expression.
Bolino, A., Seri, M., Caroli, F., Eubanks, J., Srinivasan, J., Mandich, P., Schenone, A., Quattrone, A., Romeo, G., Catterall, W. A., Devoto, M. Exclusion of the SCN2B gene as candidate for CMT4B. Europ. J. Hum. Genet. 6: 629-634, 1998. [PubMed: 9887383] [Full Text: https://doi.org/10.1038/sj.ejhg.5200220]
Chen, C., Bharucha, V., Chen, Y., Westenbroek, R. E., Brown, A., Malhotra, J. D., Jones, D., Avery, C., Gillespie, P. J., III, Kazen-Gillespie, K. A., Kazarinova-Noyes, K., Shrager, P., Saunders, T. L., Macdonald, R. L., Ransom, B. R., Scheur, T., Catterall, W. A., Isom, L. L. Reduced sodium channel density, altered voltage, dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta-2-subunits. Proc. Nat. Acad. Sci. 99: 17072-17077, 2002. [PubMed: 12481039] [Full Text: https://doi.org/10.1073/pnas.212638099]
Eubanks, J., Srinivasan, J., Dinulos, M. B., Disteche, C. M., Catterall, W. A. Structure and chromosomal localization of the beta2 subunit of the human brain sodium channel. Neuroreport 8: 2775-2779, 1997. [PubMed: 9295116] [Full Text: https://doi.org/10.1097/00001756-199708180-00025]
Imai, K., Kingsley, D. M. Mouse chromosome 9. Mammalian Genome 5: S139-S153, 1994. [PubMed: 7719002]
Isom, L. L., Ragsdale, D. S., De Jongh, K. S., Westenbroek, R. E., Reber, B. F. X., Scheuer, T., Catterall, W. A. Structure and function of the beta-2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83: 433-442, 1995. [PubMed: 8521473] [Full Text: https://doi.org/10.1016/0092-8674(95)90121-3]
Jones, J. M., Meisler, M. H., Isom, L. L. Scn2b, a voltage-gated sodium channel beta-2 gene on mouse chromosome 9. Genomics 34: 258-259, 1996. [PubMed: 8661062] [Full Text: https://doi.org/10.1006/geno.1996.0279]
Kim, D. Y., Carey, B. W., Wang, H., Ingano, L. A. M., Binshtok, A. M., Wertz, M. H., Pettingell, W. H., He, P., Lee, V. M.-Y., Woolf, C. J., Kovacs, D. M. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nature Cell Biol. 9: 755-764, 2007. [PubMed: 17576410] [Full Text: https://doi.org/10.1038/ncb1602]
Riuro, H., Beltran-Alvarez, P., Tarradas, A., Selga, E., Campuzano, O., Verges, M., Pagans, S., Iglesias, A., Brugada, J., Brugada, P., Vazquez, F. M., Perez, G. J., Scornik, F. S., Brugada, R. A missense mutation in the sodium channel beta-2 subunit reveals SCN2B as a new candidate gene for Brugada syndrome. Hum. Mutat. 34: 961-966, 2013. [PubMed: 23559163] [Full Text: https://doi.org/10.1002/humu.22328]
Watanabe, H., Darbar, D., Kaiser, D. W., Jiramongkolchai, K., Chopra, S., Donahue, B. S., Kannankeril, P. J., Roden, D. M. Mutations in sodium channel beta-1- and beta-2-subunits associated with atrial fibrillation. Circ. Arrhythm. Electrophysiol. 2: 268-278, 2009. [PubMed: 19808477] [Full Text: https://doi.org/10.1161/CIRCEP.108.779181]