Alternative titles; symbols
HGNC Approved Gene Symbol: SCN3B
Cytogenetic location: 11q24.1 Genomic coordinates (GRCh38) : 11:123,629,188-123,654,624 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q24.1 | Atrial fibrillation, familial, 16 | 613120 | Autosomal dominant | 3 |
| Brugada syndrome 7 | 613120 | Autosomal dominant | 3 |
Voltage-sensitive sodium channel beta subunits, such as SCN3B, are auxiliary components that regulate the ion-conducting alpha subunits (summary by Morgan et al., 2000).
Morgan et al. (2000) cloned rat Scn3b and, using the rat sequence as probe, isolated human SCN3B from a striatal cDNA library. The deduced 215-amino acid SCN3B protein has an N-terminal signal sequence, an extracellular N-terminal domain, a single membrane-spanning region, and a C-terminal cytoplasmic region. The extracellular domain shows homology to proteins that adopt a V-type Ig fold, which is composed of 10 beta strands that form 2 antiparallel sheets. Northern blot analysis of rat tissues detected a 4.0-kb transcript in brain, and RT-PCR detected expression also in rat adrenal gland and kidney. In situ hybridization of rat brain detected highest expression of Scn3b in forebrain structures and in the hippocampus. In most areas, expression of Scn3b complemented the expression of Scn1b (600235). The exception was hippocampus, where both subunits were expressed at high levels.
By Western blot analysis, Hu et al. (2009) confirmed the presence of the beta-3 subunit of the sodium channel in human ventricular myocardium.
By quantitative PCR analysis, Olesen et al. (2011) demonstrated expression of SCN3B in human atria and ventricles.
By functional expression of rat Scn3b or Scn1b with rat Scn2a (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 Scn3b inactivating channel opening more slowly than Scn1b.
Wang et al. (2010) noted that the SCN3B gene contains 5 coding exons.
By radiation hybrid analysis, Morgan et al. (2000) mapped the SCN3B gene to chromosome 11q23.3.
Brugada Syndrome 7
In a 64-year-old man with Brugada syndrome (BRGDA7; 613120), who was negative for mutation in 9 'Brugada-susceptibility' genes, Hu et al. (2009) identified heterozygosity for a missense mutation in the SCN3B gene.
Atrial Fibrillation 16
Wang et al. (2010) sequenced the SCN3B gene in 477 patients with atrial fibrillation (AF) from the GeneID Han Chinese population, and identified 1 patient with lone AF (ATFB16; see 613120) who was heterozygous for a missense mutation (A130V; 608214.0003).
Olesen et al. (2011) analyzed the SCN3B and SCN4B (608256) genes in 192 unrelated Danish patients with early-onset lone AF, and identified 3 missense mutations in the SCN3B gene (see, e.g., 608214.0004 and 608214.0005), including the L10P substitution (608214.0001) that had previously been found in a patient with Brugada syndrome. The 3 mutation-positive patients were screened for mutations in 10 known AF-associated genes; a missense variant in the SCN5A gene that did not appear to be pathogenic was detected in 1 of the patients (see 608214.0004). A flecainide test performed in 1 of the patients did not induce a Brugada-like ECG pattern.
Possible Association with Ventricular Fibrillation
In a 20-year-old man who had a single episode of ventricular fibrillation and who was negative for mutation in 6 cardiac arrhythmia-associated genes, Valdivia et al. (2010) identified a heterozygous missense mutation in the SCN3B gene (V54G; 608214.0002). However, the mutation was also detected in his unaffected mother.
Brugada Syndrome 7
In a 64-year-old man with Brugada syndrome-7 (613120), Hu et al. (2009) identified heterozygosity for a 29T-C transition in exon 1 of the SCN3B gene, resulting in a leu10-to-pro (L10P) substitution at a highly conserved residue in the extracellular domain. The mutation was not found in the proband's unaffected brother or in 360 Caucasian, 120 Turkish, and 112 Sephardic Jewish reference alleles. Coexpression of wildtype SCN5A (600163) and SCN1B (600235) with mutant SCN3B resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared to all-wildtype coexpression. Confocal microscopy revealed that when coexpressed with wildtype SCN1B and L10P-mutant SCN3B, wildtype SCN5A channels remain trapped in intracellular organelles rather than localizing to the cell surface.
Atrial Fibrillation 16
In a Danish man with persistent atrial fibrillation (ATFB16; see 613120) that began at 35 years of age, Olesen et al. (2011) identified heterozygosity for the L10P mutation in the SCN3B gene. There was no family history of AF; his mother, who did not carry the mutation, had premature atrial complexes on ECG. The patient declined flecainide testing.
This variant is classified as a variant of unknown significance because its contribution to ventricular fibrillation (see 603829) has not been confirmed.
In a 20-year-old man who had a single episode of ventricular fibrillation, Valdivia et al. (2010) identified heterozygosity for a 161T-G transversion in the SCN3B gene, resulting in a val54-to-gly (V54G) substitution at a highly conserved residue in the extracellular domain of the Nav-beta-3 subunit. The mutation, which was also detected in the patient's asymptomatic mother, was not found in 800 reference alleles. Functional analysis in HEK293 cells showed changes in kinetics that were consistent with a loss of function, including a significant decrease in peak sodium current density with the mutant compared to wildtype, as well as a depolarizing shift of the voltage dependence of activation and loss of the normal negative shift at the midpoint of inactivation. Coimmunoprecipitation experiments showed association of Nav-beta-3 with Nav1.5 (SCN5A; 600163), and immunocytochemistry demonstrated a dramatic decrease in trafficking to the plasma membrane when coexpressed with the V54G Nav-beta-3 mutant. The patient was otherwise healthy when he lost consciousness while playing basketball at age 20 years, and was resuscitated from ventricular fibrillation by emergency responders. He had no history of syncopal episodes, and there was no family history of sudden death. Subsequent cardiac evaluation was negative except for an epsilon wave in the right precordial leads on electrocardiography (ECG). A cardioverter-defibrillator was implanted, and no subsequent events occurred over 8 years of follow-up. The proband's asymptomatic mother displayed J-point elevation on ECG.
In a 46-year-old Han Chinese man with paroxysmal lone atrial fibrillation (ATFB16; see 613120), who had no other cardiac or systemic abnormalities, Wang et al. (2010) identified heterozygosity for a 389C-T transition in exon 3 of the SCN3B gene, resulting in an ala130-to-val (A130V) substitution. Family members declined genetic analysis; however, the mutation was not found in 500 ethnically matched controls. Functional analysis in HEK293 cells showed that the A130V mutant significantly decreased the sodium current density by a dominant-negative mechanism.
In a Danish man with persistent atrial fibrillation (ATFB16; see 613120), who had onset of lone AF at 39 years of age, Olesen et al. (2011) identified heterozygosity for a c.17G-A transition in the SCN3B gene, resulting in an arg6-to-lys (R6K) substitution at a highly conserved residue. The mutation was not found in 432 control alleles. Coexpression of wildtype SCN5A (600163) and SCN1B (600235) with R6K-mutant SCN3B resulted in a significant negative shift of the voltage dependence of inactivation compared to wildtype. The patient's deceased mother and aunt had permanent AF late in life. The patient was highly symptomatic, and had undergone 12 DC conversions as well as 3 radiofrequency ablation procedures. Flecainide testing did not induce a Brugada-like ECG pattern. Analysis of 10 known AF-associated genes revealed that the patient also carried a missense variant in the SCN5A gene; the SCN5A variant caused no changes in activation/inactivation parameters or in peak current density and was not believed to be pathogenic.
In a Danish man with paroxysmal atrial fibrillation (ATFB16; see 613120), who had onset of lone AF at 36 years of age, Olesen et al. (2011) identified heterozygosity for a c.482T-C transition in the SCN3B gene, resulting in a met161-to-thr (M161T) substitution at a highly conserved residue. The mutation was not found in 432 control alleles. Coexpression of wildtype SCN5A (600163) and SCN1B (600235) with M161T-mutant SCN3B resulted in a 57% decrease in peak current density compared to wildtype. There was no family history of AF; Holter monitoring showed a large number of premature ventricular complexes. The patient was not available for flecainide testing.
Hu, D., Barajas-Martinez, H., Burashnikov, E., Springer, M., Wu, Y., Varro, A., Pfeiffer, R., Koopmann, T. T., Cordeiro, J. M., Guerchicoff, A., Pollevick, G. D., Antzelevitch, C. A mutation in the beta-3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype. Circ. Cardiovasc. Genet. 2: 270-278, 2009. [PubMed: 20031595] [Full Text: https://doi.org/10.1161/CIRCGENETICS.108.829192]
Morgan, K., Stevens, E. B., Shah, B., Cox, P. J., Dixon, A. K., Lee, K., Pinnock, R. D., Hughes, J., Richardson, P. J., Mizuguchi, K., Jackson, A. P. Beta-3: an additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics. Proc. Nat. Acad. Sci. 97: 2308-2313, 2000. [PubMed: 10688874] [Full Text: https://doi.org/10.1073/pnas.030362197]
Olesen, M. S., Jespersen, T., Nielsen, J. B., Liang, B., Moller, D. V., Hedley, P., Christiansen, M., Varro, A., Olesen, S.-P., Haunso, S., Schmitt, N., Svendsen, J. H. Mutations in sodium channel beta-subunit SCN3B are associated with early-onset lone atrial fibrillation. Cardiovasc. Res. 89: 786-793, 2011. [PubMed: 21051419] [Full Text: https://doi.org/10.1093/cvr/cvq348]
Valdivia, C. R., Medeiros-Domingo, A., Ye, B., Shen, W.-K., Algiers, T. J., Ackerman, M. J., Makielski, J. C. Loss-of-function mutation of the SCN3B-encoded sodium channel beta-3 subunit associated with a case of idiopathic ventricular fibrillation. Cardiovasc. Res. 86: 392-400, 2010. [PubMed: 20042427] [Full Text: https://doi.org/10.1093/cvr/cvp417]
Wang, P., Yang, Q., Wu, X., Yang, Y., Shi, L., Wang, C., Wu, G., Xia, Y., Yang, B., Zhang, R., Xu, C., Cheng, X., Li, S., Zhao, Y., Fu, F., Liao, Y., Fang, F., Chen, Q., Tu, X., Wang, Q. K. Functional dominant-negative mutation of sodium channel subunit gene SCN3B associated with atrial fibrillation in a Chinese GeneID population. Biochem. Biophys. Res. Commun. 398: 98-104, 2010. [PubMed: 20558140] [Full Text: https://doi.org/10.1016/j.bbrc.2010.06.042]