* 608256

SODIUM VOLTAGE-GATED CHANNEL, BETA SUBUNIT 4; SCN4B


Alternative titles; symbols

SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, BETA SUBUNIT


HGNC Approved Gene Symbol: SCN4B

Cytogenetic location: 11q23.3     Genomic coordinates (GRCh38): 11:118,133,377-118,152,823 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q23.3 Atrial fibrillation, familial, 17 611819 AD 3
Long QT syndrome 10 611819 AD 3

TEXT

Description

Sodium channel beta subunits, such as SCN4B, are auxiliary subunits that alter the channel kinetics of voltage-gated alpha subunits (see 182389).


Cloning and Expression

By searching EST databases for sequences similar to voltage-gated beta subunits, Yu et al. (2003) identified SCN4B. The deduced 228-amino acid protein has a calculated molecular mass of about 22 kD. SCN4B has an N-terminal signal peptide, a large extracellular domain predicted to form an Ig-like fold, a single transmembrane alpha helix, and a short cytoplasmic C terminus. Two conserved cysteines likely form an intramolecular disulfide bond that stabilizes the large extracellular domain, and an unpaired cysteine likely forms a disulfide linkage with the alpha subunit. SCN4B shares 35% amino acid identity with SCN2B (601327) and 20 to 22% identity with SCN1B (600235) and SCN3B (608214). SCN4B shares 80% amino acid identity with rat and mouse Scn4b. Quantitative RT-PCR analysis, in situ hybridization, and immunocytochemical analysis of rat tissues detected wide expression of Scn4b in neurons in the brain and spinal cord and in some sensory neurons.

By quantitative PCR analysis, Olesen et al. (2011) demonstrated expression of SCN4B in human atria and ventricles.


Gene Function

By Western blot analysis of proteins separated under nonreducing conditions, Yu et al. (2003) found that SCN4B had an apparent molecular mass of more than 250 kD due to covalent linkage with a cotransfected alpha subunit, SCN2A (182390). Under reducing conditions, the apparent molecular mass was 38 kD, similar to the masses of the mature glycosylated forms of other beta subunits. Whole-cell recording of sodium currents in cotransfected embryonic kidney cells indicated that SCN4B could alter the channel properties of SCN2A and shift the voltage dependence of activation in the hyperpolarizing direction without altering the voltage dependence of inactivation. Coexpression of SCN4B with skeletal muscle SCN4A (603967) caused a modest negative shift in the voltage dependence of activation with little or no effect on the voltage dependence of inactivation. SCN4B had little effect on the channel kinetics of cardiac SCN5A (600163).


Gene Structure

Yu et al. (2003) determined that the SCN4B gene contains 5 exons and spans 19.5 kb.


Mapping

By genomic sequence analysis, Yu et al. (2003) mapped the SCN4B gene to chromosome 11q23, about 12.5 kb downstream of the SCN2B gene.


Molecular Genetics

In affected members of a 4-generation Mexican mestizo family with long QT syndrome (LQT10; 611819) who were negative for mutation in the 9 known LQTS genes (see LQT1, 192500), Medeiros-Domingo et al. (2007) identified a heterozygous missense mutation in the SCN4B gene (L179F; 608256.0001). The mutation segregated with the phenotype with incomplete penetrance, but was not found in 800 control alleles, 400 of which were ethnically matched. Studies in HEK293 cells demonstrated that the mutant channel caused an 8-fold increase in late sodium current compared to wildtype.

In 2 Han Chinese families segregating autosomal dominant atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for 2 different missense mutations in the SCN4B gene, V162G (608256.0002) and I166L (608256.0003), respectively. The mutations, which segregated with disease in each of the families, were not found in 200 ethnically matched controls. In the family with the V162G mutation, all 3 individuals with atrial fibrillation also had corrected QT intervals that met the criteria for long QT syndrome.


ALLELIC VARIANTS ( 3 Selected Examples):

.0001 LONG QT SYNDROME 10

SCN4B, LEU179PHE
  
RCV000002563

In affected members of a 4-generation Mexican mestizo family with a history of sudden death and long QT syndrome (LQT10; 611819) who were negative for mutation in the 9 known LQTS genes (see LQT1; 192500), Medeiros-Domingo et al. (2007) identified a heterozygous 535C-T transition in the SCN4B gene, resulting in a leu179-to-phe (L179F) substitution at a conserved residue. The mutation segregated with the phenotype with incomplete penetrance, but was not found in 800 control alleles, 400 of which were ethnically matched. Studies in transiently transfected HEK293 cells demonstrated that the mutant channel caused an 8-fold increase in late sodium current compared to wildtype.


.0002 ATRIAL FIBRILLATION, FAMILIAL, 17

SCN4B, VAL162GLY
  
RCV000128816

In a Han Chinese mother and 2 sons with atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for a c.485T-G transversion in the SCN4B gene, resulting in a val162-to-gly (V162G) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in 200 ethnically matched controls, or in the dbSNP database. All 3 affected individuals also had prolonged corrected QT intervals that fulfilled the criteria for long QT syndrome.


.0003 ATRIAL FIBRILLATION, FAMILIAL, 17

SCN4B, ILE166LEU
  
RCV000128817

In 3 affected individuals over 3 generations of a Han Chinese family with atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for a c.496A-C transversion in the SCN4B gene, resulting in an ile166-to-leu (I166L) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in 200 ethnically matched controls, or in the dbSNP database. Corrected QT intervals were within the normal range in affected members of this family.


REFERENCES

  1. Li, R.-G., Wang, Q., Xu, Y.-J., Zhang, M., Qu, X.-K., Liu, X., Fang, W.-Y., Yang, Y.-Q. Mutations of the SCN4B-encoded sodium channel beta-4 subunit in familial atrial fibrillation. Int. J. Molec. Med. 32: 144-150, 2013. [PubMed: 23604097, related citations] [Full Text]

  2. Medeiros-Domingo, A., Kaku, T., Tester, D. J., Iturralde-Torres, P., Itty, A., Ye, B., Valdivia, C., Ueda, K., Canizales-Quinteros, S., Tusie-Luna, M. T., Makielski, J. C., Ackerman, M. J. SCN4B-encoded sodium channel beta-4 subunit in congenital long-QT syndrome. Circulation 116: 134-142, 2007. [PubMed: 17592081, images, related citations] [Full Text]

  3. 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, related citations] [Full Text]

  4. Yu, F. H., Westenbroek, R. E., Silos-Santiago, I., McCormick, K. A., Lawson, D., Ge, P., Ferriera, H., Lilly, J., DiStefano, P. S., Catterall, W. A., Scheuer, T., Curtis, R. Sodium channel beta-4, a new disulfide-linked auxiliary subunit with similarity to beta-2. J. Neurosci. 23: 7577-7585, 2003. [PubMed: 12930796, related citations] [Full Text]


Marla J. F. O'Neill - updated : 7/22/2014
Marla J. F. O'Neill - updated : 7/22/2014
Marla J. F. O'Neill - updated : 2/12/2008
Creation Date:
Patricia A. Hartz : 11/13/2003
carol : 09/01/2020
alopez : 07/23/2014
carol : 7/23/2014
mcolton : 7/22/2014
mcolton : 7/22/2014
wwang : 2/26/2008
terry : 2/12/2008
mgross : 11/13/2003

* 608256

SODIUM VOLTAGE-GATED CHANNEL, BETA SUBUNIT 4; SCN4B


Alternative titles; symbols

SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, BETA SUBUNIT


HGNC Approved Gene Symbol: SCN4B

Cytogenetic location: 11q23.3     Genomic coordinates (GRCh38): 11:118,133,377-118,152,823 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
11q23.3 Atrial fibrillation, familial, 17 611819 Autosomal dominant 3
Long QT syndrome 10 611819 Autosomal dominant 3

TEXT

Description

Sodium channel beta subunits, such as SCN4B, are auxiliary subunits that alter the channel kinetics of voltage-gated alpha subunits (see 182389).


Cloning and Expression

By searching EST databases for sequences similar to voltage-gated beta subunits, Yu et al. (2003) identified SCN4B. The deduced 228-amino acid protein has a calculated molecular mass of about 22 kD. SCN4B has an N-terminal signal peptide, a large extracellular domain predicted to form an Ig-like fold, a single transmembrane alpha helix, and a short cytoplasmic C terminus. Two conserved cysteines likely form an intramolecular disulfide bond that stabilizes the large extracellular domain, and an unpaired cysteine likely forms a disulfide linkage with the alpha subunit. SCN4B shares 35% amino acid identity with SCN2B (601327) and 20 to 22% identity with SCN1B (600235) and SCN3B (608214). SCN4B shares 80% amino acid identity with rat and mouse Scn4b. Quantitative RT-PCR analysis, in situ hybridization, and immunocytochemical analysis of rat tissues detected wide expression of Scn4b in neurons in the brain and spinal cord and in some sensory neurons.

By quantitative PCR analysis, Olesen et al. (2011) demonstrated expression of SCN4B in human atria and ventricles.


Gene Function

By Western blot analysis of proteins separated under nonreducing conditions, Yu et al. (2003) found that SCN4B had an apparent molecular mass of more than 250 kD due to covalent linkage with a cotransfected alpha subunit, SCN2A (182390). Under reducing conditions, the apparent molecular mass was 38 kD, similar to the masses of the mature glycosylated forms of other beta subunits. Whole-cell recording of sodium currents in cotransfected embryonic kidney cells indicated that SCN4B could alter the channel properties of SCN2A and shift the voltage dependence of activation in the hyperpolarizing direction without altering the voltage dependence of inactivation. Coexpression of SCN4B with skeletal muscle SCN4A (603967) caused a modest negative shift in the voltage dependence of activation with little or no effect on the voltage dependence of inactivation. SCN4B had little effect on the channel kinetics of cardiac SCN5A (600163).


Gene Structure

Yu et al. (2003) determined that the SCN4B gene contains 5 exons and spans 19.5 kb.


Mapping

By genomic sequence analysis, Yu et al. (2003) mapped the SCN4B gene to chromosome 11q23, about 12.5 kb downstream of the SCN2B gene.


Molecular Genetics

In affected members of a 4-generation Mexican mestizo family with long QT syndrome (LQT10; 611819) who were negative for mutation in the 9 known LQTS genes (see LQT1, 192500), Medeiros-Domingo et al. (2007) identified a heterozygous missense mutation in the SCN4B gene (L179F; 608256.0001). The mutation segregated with the phenotype with incomplete penetrance, but was not found in 800 control alleles, 400 of which were ethnically matched. Studies in HEK293 cells demonstrated that the mutant channel caused an 8-fold increase in late sodium current compared to wildtype.

In 2 Han Chinese families segregating autosomal dominant atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for 2 different missense mutations in the SCN4B gene, V162G (608256.0002) and I166L (608256.0003), respectively. The mutations, which segregated with disease in each of the families, were not found in 200 ethnically matched controls. In the family with the V162G mutation, all 3 individuals with atrial fibrillation also had corrected QT intervals that met the criteria for long QT syndrome.


ALLELIC VARIANTS 3 Selected Examples):

.0001   LONG QT SYNDROME 10

SCN4B, LEU179PHE
SNP: rs121434386, ClinVar: RCV000002563

In affected members of a 4-generation Mexican mestizo family with a history of sudden death and long QT syndrome (LQT10; 611819) who were negative for mutation in the 9 known LQTS genes (see LQT1; 192500), Medeiros-Domingo et al. (2007) identified a heterozygous 535C-T transition in the SCN4B gene, resulting in a leu179-to-phe (L179F) substitution at a conserved residue. The mutation segregated with the phenotype with incomplete penetrance, but was not found in 800 control alleles, 400 of which were ethnically matched. Studies in transiently transfected HEK293 cells demonstrated that the mutant channel caused an 8-fold increase in late sodium current compared to wildtype.


.0002   ATRIAL FIBRILLATION, FAMILIAL, 17

SCN4B, VAL162GLY
SNP: rs587777559, ClinVar: RCV000128816

In a Han Chinese mother and 2 sons with atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for a c.485T-G transversion in the SCN4B gene, resulting in a val162-to-gly (V162G) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in 200 ethnically matched controls, or in the dbSNP database. All 3 affected individuals also had prolonged corrected QT intervals that fulfilled the criteria for long QT syndrome.


.0003   ATRIAL FIBRILLATION, FAMILIAL, 17

SCN4B, ILE166LEU
SNP: rs587777560, ClinVar: RCV000128817

In 3 affected individuals over 3 generations of a Han Chinese family with atrial fibrillation (ATFB17; see 611819), Li et al. (2013) identified heterozygosity for a c.496A-C transversion in the SCN4B gene, resulting in an ile166-to-leu (I166L) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in 200 ethnically matched controls, or in the dbSNP database. Corrected QT intervals were within the normal range in affected members of this family.


REFERENCES

  1. Li, R.-G., Wang, Q., Xu, Y.-J., Zhang, M., Qu, X.-K., Liu, X., Fang, W.-Y., Yang, Y.-Q. Mutations of the SCN4B-encoded sodium channel beta-4 subunit in familial atrial fibrillation. Int. J. Molec. Med. 32: 144-150, 2013. [PubMed: 23604097] [Full Text: https://doi.org/10.3892/ijmm.2013.1355]

  2. Medeiros-Domingo, A., Kaku, T., Tester, D. J., Iturralde-Torres, P., Itty, A., Ye, B., Valdivia, C., Ueda, K., Canizales-Quinteros, S., Tusie-Luna, M. T., Makielski, J. C., Ackerman, M. J. SCN4B-encoded sodium channel beta-4 subunit in congenital long-QT syndrome. Circulation 116: 134-142, 2007. [PubMed: 17592081] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.659086]

  3. 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]

  4. Yu, F. H., Westenbroek, R. E., Silos-Santiago, I., McCormick, K. A., Lawson, D., Ge, P., Ferriera, H., Lilly, J., DiStefano, P. S., Catterall, W. A., Scheuer, T., Curtis, R. Sodium channel beta-4, a new disulfide-linked auxiliary subunit with similarity to beta-2. J. Neurosci. 23: 7577-7585, 2003. [PubMed: 12930796] [Full Text: https://doi.org/10.1523/JNEUROSCI.23-20-07577.2003]


Contributors:
Marla J. F. O'Neill - updated : 7/22/2014
Marla J. F. O'Neill - updated : 7/22/2014
Marla J. F. O'Neill - updated : 2/12/2008

Creation Date:
Patricia A. Hartz : 11/13/2003

Edit History:
carol : 09/01/2020
alopez : 07/23/2014
carol : 7/23/2014
mcolton : 7/22/2014
mcolton : 7/22/2014
wwang : 2/26/2008
terry : 2/12/2008
mgross : 11/13/2003