The Experts below are selected from a list of 702 Experts worldwide ranked by ideXlab platform
Lori L Isom - One of the best experts on this subject based on the ideXlab platform.
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Voltage-Gated Sodium Channel β Subunits and Their Related Diseases
Handbook of experimental pharmacology, 2017Co-Authors: Alexandra A. Bouza, Lori L IsomAbstract:Voltage-gated sodium channels are protein complexes comprised of one pore forming α subunit and two, non-pore forming, β subunits. The voltage-gated sodium channel β subunits were originally identified to function as auxiliary subunits, which modulate the gating, kinetics, and localization of the ion channel pore. Since that time, the five β subunits have been shown to play crucial roles as multifunctional signaling molecules involved in cell adhesion, cell migration, neuronal pathfinding, fasciculation, and neurite outgrowth. Here, we provide an overview of the evidence implicating the β subunits in their conducting and non-conducting roles. Mutations in the β subunit genes (SCN1B–SCN4B) have been linked to a variety of diseases. These include cancer, epilepsy, cardiac arrhythmias, sudden infant death syndrome/sudden unexpected death in epilepsy, neuropathic pain, and multiple neurodegenerative disorders. β subunits thus provide novel therapeutic targets for future drug discovery.
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Sodium Channel β1 Subunits: Overachievers of the Ion Channel Family
Biophysical Journal, 2014Co-Authors: Lori L IsomAbstract:Voltage gated Na+ channels in mammals contain a pore-forming alpha subunit and one or more beta subunits. There are five mammalian beta subunits in total: beta1, beta1B, beta2, beta3, and beta4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, beta1B, the subunits are type I topology transmembrane proteins. In contrast, beta1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC beta subunits are multifunctional. While they do not form the ion channel pore, beta subunits alter gating, voltage-dependence, and kinetics of VGSC alpha subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, beta subunits are members of the immunoglobulin superfamily of cell adhesion molecules and regulate cell adhesion and migration. Beta subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of beta subunits is beta1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and gamma-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. Beta subunits are emerging as key players in a wide variety of pathophysiologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington's disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. Beta subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some beta subunit functions may operate independent of alpha subunits. Thus, beta subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.
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Modulation of Kv1 Voltage-Gated Potassium Channels by Sodium Channel Beta Subunits
Biophysical Journal, 2012Co-Authors: Hai M. Nguyen, Lori L Isom, Jeffrey D. Calhoun, Alan L. Goldin, George K. ChandyAbstract:Sodium channel beta subunits (SCN1b-SCN4B) are integral members of voltage-gated sodium channel (VGSC)-complexes at nodes of Ranvier, axon initial segments, and cardiac intercalated disks, where they modulate the function of VGSCs. Mutations of these genes results in neurological (e.g. epilepsy) and cardiovascular (e.g. Brugada syndrome) diseases. Here we report that SCN1b modulates the Kv1-subfamily of K+ channels, each in a unique fashion, when co-expressed in Xenopus oocytes or mammalian cells (Table). SCN2b, but not SCN3b, has similar modulatory properties. Pull-down experiments show that SCN1b is physically coupled to Kv1 channels. Using chimeras of SCN1b and the myelin Po protein, we demonstrate that the external domain of SCN1b is essential for channel modulation. Two known epilepsy-causing mutations in the Ig-domain of SCN1b, R85C and C121W, disrupt Kv1 channel-modulation. Thus, sodium channel beta subunits may regulate action potential firing and propagation in normal and diseased conditions by modulating the function of both VGSCs and Kv channels.
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na channel β subunits overachievers of the ion channel family
Frontiers in Pharmacology, 2011Co-Authors: William J. Brackenbury, Lori L IsomAbstract:Voltage gated Na+ channels (VGSCs) in mammals contain a pore-forming α subunit and one or more β subunits. There are five mammalian β subunits in total: β1, β1B, β2, β3, and β4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, β1B, the β subunits are type I topology transmembrane proteins. In contrast, β1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC β subunits are multifunctional. While they do not form the ion channel pore, β subunits alter gating, voltage-dependence, and kinetics of VGSC α subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, β subunits are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) and regulate cell adhesion and migration. β subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of β subunits is β1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and γ-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. β subunits are emerging as key players in a wide variety of pathophysiologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington’s disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. β subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some β subunit functions may operate independent of α subunits. Thus, β subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.
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Na+ Channel β Subunits: Overachievers of the Ion Channel Family
Frontiers in pharmacology, 2011Co-Authors: William J. Brackenbury, Lori L IsomAbstract:Voltage gated Na+ channels (VGSCs) in mammals contain a pore-forming α subunit and one or more β subunits. There are five mammalian β subunits in total: β1, β1B, β2, β3, and β4, encoded by four genes: SCN1B-SCN4B. With the exception of the SCN1B splice variant, β1B, the β subunits are type I topology transmembrane proteins. In contrast, β1B lacks a transmembrane domain and is a secreted protein. A growing body of work shows that VGSC β subunits are multifunctional. While they do not form the ion channel pore, β subunits alter gating, voltage-dependence, and kinetics of VGSC α subunits and thus regulate cellular excitability in vivo. In addition to their roles in channel modulation, β subunits are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) and regulate cell adhesion and migration. β subunits are also substrates for sequential proteolytic cleavage by secretases. An example of the multifunctional nature of β subunits is β1, encoded by SCN1B, that plays a critical role in neuronal migration and pathfinding during brain development, and whose function is dependent on Na+ current and γ-secretase activity. Functional deletion of SCN1B results in Dravet Syndrome, a severe and intractable pediatric epileptic encephalopathy. β subunits are emerging as key players in a wide variety of pathophysiologies, including epilepsy, cardiac arrhythmia, multiple sclerosis, Huntington’s disease, neuropsychiatric disorders, neuropathic and inflammatory pain, and cancer. β subunits mediate multiple signaling pathways on different timescales, regulating electrical excitability, adhesion, migration, pathfinding, and transcription. Importantly, some β subunit functions may operate independent of α subunits. Thus, β subunits perform critical roles during development and disease. As such, they may prove useful in disease diagnosis and therapy.
Noriyoshi Teramoto - One of the best experts on this subject based on the ideXlab platform.
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Effects of 4,9-anhydrotetrodotoxin on voltage-gated Na^+ channels of mouse vas deferens myocytes and recombinant Na_V1.6 channels
Naunyn-Schmiedeberg's Archives of Pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Mari Yotsu-yamashita, Noriyoshi TeramotoAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na^+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes ( Scn2b – SCN4B ). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na^+ current peak amplitude in myocytes (i.e., native I_Na) were compared with its inhibitory potency on recombinant Na_V1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native I_Na and recombinant Na_V1.6 expressed in HEK293 cells (i.e., recombinant I_Na). The current decay of native I_Na was similar to the recombinant Na_V1.6 current co-expressed with β_1-subunits. The current-voltage (I-V) relationships of native I_Na were similar to those of recombinant Na_V1.6 currents co-expressed with β_1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native I_Na ( K _ i = 510 nM), recombinant I_Na ( K _ i = 112 nM), and recombinant I_Na co-expressed with β_1-subunits ( K _ i = 92 nM). The half-maximal (V_half) activation and inactivation of native I_Na values were similar to those observed in recombinant I_Na co-expressed with β_1-subunits. These results suggest that β_1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native I_Na but also recombinant I_Na and recombinant I_Na co-expressed with β_1-subunits in a concentration-dependent manner.
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effects of 4 9 anhydrotetrodotoxin on voltage gated na channels of mouse vas deferens myocytes and recombinant nav1 6 channels
Naunyn-schmiedebergs Archives of Pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Noriyoshi Teramoto, Mari YotsuyamashitaAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes (Scn2b – SCN4B). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na+ current peak amplitude in myocytes (i.e., native INa) were compared with its inhibitory potency on recombinant NaV1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native INa and recombinant NaV1.6 expressed in HEK293 cells (i.e., recombinant INa). The current decay of native INa was similar to the recombinant NaV1.6 current co-expressed with β1-subunits. The current-voltage (I-V) relationships of native INa were similar to those of recombinant NaV1.6 currents co-expressed with β1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native INa (K i = 510 nM), recombinant INa (K i = 112 nM), and recombinant INa co-expressed with β1-subunits (K i = 92 nM). The half-maximal (Vhalf) activation and inactivation of native INa values were similar to those observed in recombinant INa co-expressed with β1-subunits. These results suggest that β1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native INa but also recombinant INa and recombinant INa co-expressed with β1-subunits in a concentration-dependent manner.
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Effects of 4,9-anhydrotetrodotoxin on voltage-gated Na+ channels of mouse vas deferens myocytes and recombinant NaV1.6 channels.
Naunyn-Schmiedeberg's archives of pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Mari Yotsu-yamashita, Noriyoshi TeramotoAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes (Scn2b – SCN4B). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na+ current peak amplitude in myocytes (i.e., native INa) were compared with its inhibitory potency on recombinant NaV1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native INa and recombinant NaV1.6 expressed in HEK293 cells (i.e., recombinant INa). The current decay of native INa was similar to the recombinant NaV1.6 current co-expressed with β1-subunits. The current-voltage (I-V) relationships of native INa were similar to those of recombinant NaV1.6 currents co-expressed with β1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native INa (K i = 510 nM), recombinant INa (K i = 112 nM), and recombinant INa co-expressed with β1-subunits (K i = 92 nM). The half-maximal (Vhalf) activation and inactivation of native INa values were similar to those observed in recombinant INa co-expressed with β1-subunits. These results suggest that β1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native INa but also recombinant INa and recombinant INa co-expressed with β1-subunits in a concentration-dependent manner.
Morten S. Olesen - One of the best experts on this subject based on the ideXlab platform.
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The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome
Heart Rhythm, 2015Co-Authors: Bo Gregers Winkel, Stig Haunso, Yinman Wang, Morten S. Olesen, Anders G. Holst, Lei Yuan, Golnaz Sadjadieh, Bjarke Risgaard, Reza Jabbari, Mads V. HollegaardAbstract:Background Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Na v 1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown. Objective The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases. Methods DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000–2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Na v 1.5 channel complex: SCN5A , SCN1B , SCN2B , SCN3B , SCN4B , GPD1L , SNTA1 , and CAV3 . Patch-clamp analyses were performed on variants not previously characterized. Results In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3 , 1 rare variant (T78M); GPD1L , 1 rare variant (R220H); and SCN3B , 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A ) predominantly revealed increased transient and sustained sodium current. Conclusion In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.
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Mutation analysis of the candidate genes SCN1B- 4B, FHL1, and LMNA in patients with arrhythmogenic right ventricular cardiomyopathy
Applied & translational genomics, 2012Co-Authors: Lena Refsgaard, Stig Haunso, Jesper Hastrup Svendsen, Morten S. Olesen, Michael Christiansen, Daniel V. Møller, Alex Hørby ChristensenAbstract:Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes SCN1B - SCN4B , FHL1 , and LMNA in the pathogenesis of ARVC. Methods Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in SCN1B - 4B , FHL1 , and LMNA by direct sequencing and LightScanner melting curve analysis. Results A total of 28 sequence variants were identified: seven in SCN1B , three in SCN2B , two in SCN3B , two in SCN4B , four in FHL1 , and ten in LMNA . Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified. Conclusions In our limited sized cohort the six studied candidate genes were not associated with ARVC.
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Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.
Canadian Journal of Cardiology, 2012Co-Authors: Anders G. Holst, Stig Haunso, Siamak Saber, Massoud Houshmand, Yinman Wang, Jesper Hastrup Svendsen, Lena Refsgaard, E V Zaklyazminskaya, Henrik Jensen, Morten S. OlesenAbstract:Abstract Background Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B , SCN3B , MOG1 , and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B , MOG1 , CAV3 , and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data. Methods Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project (ESP) for both previously published variant-BrS associations and newly uncovered variations within the noted genes. Results A total of 42 BrS patients were screened, and 2 different nonsynonymous mutations in SCN1Bb (H162P and R214Q) were found in 2 different Danish patients. The variants were not found in 216 Danish controls, but R214Q was present in ESP data (5 of 841 alleles). No other mutations were found. Previously BrS-associated mutations in KNCD3 and SCN3B were also present in ESP data. This was not the case for MOG1 , but a nonsense polymorphism was present in 0.5% of alleles. Conclusions Our study supports the association of SCN1Bb with BrS. However, recently released exome data make some of the prior associations of BrS with genes SCN3B , MOG1 , and KCND3 less likely.
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Clinical Research Sodium Current and Potassium Transient Outward Current Genes in Brugada Syndrome: Screening and Bioinformatics
2012Co-Authors: Anders G. Holst, Stig Haunso, Siamak Saber, Massoud Houshmand, Yinman Wang, Jesper Hastrup Svendsen, Lena Refsgaard, E V Zaklyazminskaya, Henrik Jensen, Morten S. OlesenAbstract:Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B, MOG1, CAV3, and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data. Methods: Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the RESUME
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Mutations in sodium channel β-subunit SCN3B are associated with early-onset lone atrial fibrillation
Cardiovascular research, 2010Co-Authors: Morten S. Olesen, Paula L. Hedley, Michael Christiansen, Daniel V. Møller, András Varró, Thomas Jespersen, Jonas B. Nielsen, Bo Liang, Søren-peter Olesen, Stig HaunsoAbstract:Aims Atrial fibrillation (AF) is the most frequent arrhythmia. Screening of SCN5A —the gene encoding the α-subunit of the cardiac sodium channel—has indicated that disturbances of the sodium current may play a central role in the mechanism of lone AF. We tested the hypothesis that lone AF in young patients is associated with genetic mutations in SCN3B and SCN4B , the genes encoding the two β-subunits of the cardiac sodium channel. Methods and results In 192 unrelated lone AF patients, the entire coding sequence and splice junctions of SCN3B and SCN4B were bidirectionally sequenced. Three non-synonymous mutations were found in SCN3B (R6K, L10P, and M161T). Two mutations were novel (R6K and M161T). None of the mutations were present in the control group ( n = 432 alleles), nor have any been previously reported in conjunction with AF. All SCN3B mutations affected residues that are evolutionarily conserved across species. Electrophysiological studies on the SCN3B mutation were carried out and all three SCN3B mutations caused a functionally reduced sodium channel current. One synonymous variant was found in SCN4B . Conclusion In 192 young lone AF patients, we found three patients with suspected disease-causing non-synonymous mutations in SCN3B , indicating that mutations in this gene contribute to the mechanism of lone AF. The three mutations in SCN3B were investigated electrophysiologically and all led to loss of function in the sodium current, supporting the hypothesis that decreased sodium current enhances AF susceptibility.
Stig Haunso - One of the best experts on this subject based on the ideXlab platform.
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The role of the sodium current complex in a nonreferred nationwide cohort of sudden infant death syndrome
Heart Rhythm, 2015Co-Authors: Bo Gregers Winkel, Stig Haunso, Yinman Wang, Morten S. Olesen, Anders G. Holst, Lei Yuan, Golnaz Sadjadieh, Bjarke Risgaard, Reza Jabbari, Mads V. HollegaardAbstract:Background Sudden infant death syndrome (SIDS) is the most common cause of death in infants between the age of 1 month and 1 year. Rare variants in Na v 1.5 encoded by SCN5A are known to play a role in SIDS; however, the combined role of the sodium current complex is unknown. Objective The purpose of this study was to investigate the role of the sodium current complex in a nonreferred nationwide cohort of SIDS cases. Methods DNA was extracted from dried blood spot samples from the Danish Neonatal Screening Biobank. In total, 66 non-referred SIDS cases born in Denmark in the period of 2000–2006 were screened for genetic variants in the 8 major genes involved in the regulation of the Na v 1.5 channel complex: SCN5A , SCN1B , SCN2B , SCN3B , SCN4B , GPD1L , SNTA1 , and CAV3 . Patch-clamp analyses were performed on variants not previously characterized. Results In total, 8 patients (12%) had nonsynonymous rare variants in the sodium current genes. SCN5A harbored 6 rare variants (R458C, R535*, S1103Y, R1193Q, S1609L, and Q1909R); CAV3 , 1 rare variant (T78M); GPD1L , 1 rare variant (R220H); and SCN3B , 1 rare variant (L10P). Four variants were considered likely pathogenic and 5 variants of unknown significance. SCN5A R1193Q and GPD1L R220H (both considered variants of unknown significance) were present in the same infant. Functional analysis of variants not previously characterized (R458C, S1609L, and Q1909R in SCN5A ) predominantly revealed increased transient and sustained sodium current. Conclusion In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes.
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Mutation analysis of the candidate genes SCN1B- 4B, FHL1, and LMNA in patients with arrhythmogenic right ventricular cardiomyopathy
Applied & translational genomics, 2012Co-Authors: Lena Refsgaard, Stig Haunso, Jesper Hastrup Svendsen, Morten S. Olesen, Michael Christiansen, Daniel V. Møller, Alex Hørby ChristensenAbstract:Abstract Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart disease characterized by fibrofatty infiltrations in the myocardium, right and/or left ventricular involvement, and ventricular tachyarrhythmias. Although ten genes have been associated with ARVC, only about 40% of the patients have an identifiable disease-causing mutation. In the present study we aimed at investigating the involvement of the genes SCN1B - SCN4B , FHL1 , and LMNA in the pathogenesis of ARVC. Methods Sixty-five unrelated patients (55 fulfilling ARVC criteria and 10 borderline cases) were screened for variants in SCN1B - 4B , FHL1 , and LMNA by direct sequencing and LightScanner melting curve analysis. Results A total of 28 sequence variants were identified: seven in SCN1B , three in SCN2B , two in SCN3B , two in SCN4B , four in FHL1 , and ten in LMNA . Three of the variants were novel. One of the variants was non-synonymous. No disease-causing mutations were identified. Conclusions In our limited sized cohort the six studied candidate genes were not associated with ARVC.
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Sodium current and potassium transient outward current genes in Brugada syndrome: screening and bioinformatics.
Canadian Journal of Cardiology, 2012Co-Authors: Anders G. Holst, Stig Haunso, Siamak Saber, Massoud Houshmand, Yinman Wang, Jesper Hastrup Svendsen, Lena Refsgaard, E V Zaklyazminskaya, Henrik Jensen, Morten S. OlesenAbstract:Abstract Background Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B , SCN3B , MOG1 , and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B , MOG1 , CAV3 , and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data. Methods Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project (ESP) for both previously published variant-BrS associations and newly uncovered variations within the noted genes. Results A total of 42 BrS patients were screened, and 2 different nonsynonymous mutations in SCN1Bb (H162P and R214Q) were found in 2 different Danish patients. The variants were not found in 216 Danish controls, but R214Q was present in ESP data (5 of 841 alleles). No other mutations were found. Previously BrS-associated mutations in KNCD3 and SCN3B were also present in ESP data. This was not the case for MOG1 , but a nonsense polymorphism was present in 0.5% of alleles. Conclusions Our study supports the association of SCN1Bb with BrS. However, recently released exome data make some of the prior associations of BrS with genes SCN3B , MOG1 , and KCND3 less likely.
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Clinical Research Sodium Current and Potassium Transient Outward Current Genes in Brugada Syndrome: Screening and Bioinformatics
2012Co-Authors: Anders G. Holst, Stig Haunso, Siamak Saber, Massoud Houshmand, Yinman Wang, Jesper Hastrup Svendsen, Lena Refsgaard, E V Zaklyazminskaya, Henrik Jensen, Morten S. OlesenAbstract:Background: Brugada syndrome (BrS) is a primary arrhythmia syndrome characterized by the occurrence of malignant ventricular arrhythmias. Previously, the genes SCN1B, SCN3B, MOG1, and KCND3 have been associated with BrS. Recent data from exome screening efforts permit better discrimination between low-frequency genetic variants and true monogenetic disease-causing variants. We aimed to screen the genes SCN1B through SCN4B, MOG1, CAV3, and KCND3 for variations in a population of SCN5A negative Danish and Iranian BrS patients, as well as research prior associations using newly released exome data. Methods: Screening of all exons and splice sites was performed using Sanger sequencing. Bioinformatic searches were performed in the Single-nucleotide polymorphism database (build 132) and in the RESUME
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Mutations in sodium channel β-subunit SCN3B are associated with early-onset lone atrial fibrillation
Cardiovascular research, 2010Co-Authors: Morten S. Olesen, Paula L. Hedley, Michael Christiansen, Daniel V. Møller, András Varró, Thomas Jespersen, Jonas B. Nielsen, Bo Liang, Søren-peter Olesen, Stig HaunsoAbstract:Aims Atrial fibrillation (AF) is the most frequent arrhythmia. Screening of SCN5A —the gene encoding the α-subunit of the cardiac sodium channel—has indicated that disturbances of the sodium current may play a central role in the mechanism of lone AF. We tested the hypothesis that lone AF in young patients is associated with genetic mutations in SCN3B and SCN4B , the genes encoding the two β-subunits of the cardiac sodium channel. Methods and results In 192 unrelated lone AF patients, the entire coding sequence and splice junctions of SCN3B and SCN4B were bidirectionally sequenced. Three non-synonymous mutations were found in SCN3B (R6K, L10P, and M161T). Two mutations were novel (R6K and M161T). None of the mutations were present in the control group ( n = 432 alleles), nor have any been previously reported in conjunction with AF. All SCN3B mutations affected residues that are evolutionarily conserved across species. Electrophysiological studies on the SCN3B mutation were carried out and all three SCN3B mutations caused a functionally reduced sodium channel current. One synonymous variant was found in SCN4B . Conclusion In 192 young lone AF patients, we found three patients with suspected disease-causing non-synonymous mutations in SCN3B , indicating that mutations in this gene contribute to the mechanism of lone AF. The three mutations in SCN3B were investigated electrophysiologically and all led to loss of function in the sodium current, supporting the hypothesis that decreased sodium current enhances AF susceptibility.
Kohei Takahara - One of the best experts on this subject based on the ideXlab platform.
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Effects of 4,9-anhydrotetrodotoxin on voltage-gated Na^+ channels of mouse vas deferens myocytes and recombinant Na_V1.6 channels
Naunyn-Schmiedeberg's Archives of Pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Mari Yotsu-yamashita, Noriyoshi TeramotoAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na^+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes ( Scn2b – SCN4B ). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na^+ current peak amplitude in myocytes (i.e., native I_Na) were compared with its inhibitory potency on recombinant Na_V1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native I_Na and recombinant Na_V1.6 expressed in HEK293 cells (i.e., recombinant I_Na). The current decay of native I_Na was similar to the recombinant Na_V1.6 current co-expressed with β_1-subunits. The current-voltage (I-V) relationships of native I_Na were similar to those of recombinant Na_V1.6 currents co-expressed with β_1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native I_Na ( K _ i = 510 nM), recombinant I_Na ( K _ i = 112 nM), and recombinant I_Na co-expressed with β_1-subunits ( K _ i = 92 nM). The half-maximal (V_half) activation and inactivation of native I_Na values were similar to those observed in recombinant I_Na co-expressed with β_1-subunits. These results suggest that β_1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native I_Na but also recombinant I_Na and recombinant I_Na co-expressed with β_1-subunits in a concentration-dependent manner.
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effects of 4 9 anhydrotetrodotoxin on voltage gated na channels of mouse vas deferens myocytes and recombinant nav1 6 channels
Naunyn-schmiedebergs Archives of Pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Noriyoshi Teramoto, Mari YotsuyamashitaAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes (Scn2b – SCN4B). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na+ current peak amplitude in myocytes (i.e., native INa) were compared with its inhibitory potency on recombinant NaV1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native INa and recombinant NaV1.6 expressed in HEK293 cells (i.e., recombinant INa). The current decay of native INa was similar to the recombinant NaV1.6 current co-expressed with β1-subunits. The current-voltage (I-V) relationships of native INa were similar to those of recombinant NaV1.6 currents co-expressed with β1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native INa (K i = 510 nM), recombinant INa (K i = 112 nM), and recombinant INa co-expressed with β1-subunits (K i = 92 nM). The half-maximal (Vhalf) activation and inactivation of native INa values were similar to those observed in recombinant INa co-expressed with β1-subunits. These results suggest that β1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native INa but also recombinant INa and recombinant INa co-expressed with β1-subunits in a concentration-dependent manner.
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Effects of 4,9-anhydrotetrodotoxin on voltage-gated Na+ channels of mouse vas deferens myocytes and recombinant NaV1.6 channels.
Naunyn-Schmiedeberg's archives of pharmacology, 2018Co-Authors: Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Mari Yotsu-yamashita, Noriyoshi TeramotoAbstract:Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na+ channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes (Scn2b – SCN4B). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na+ current peak amplitude in myocytes (i.e., native INa) were compared with its inhibitory potency on recombinant NaV1.6 channels (expressed in HEK293 cells). A depolarizing rectangular voltage-pulse elicited a fast and transient inward native INa and recombinant NaV1.6 expressed in HEK293 cells (i.e., recombinant INa). The current decay of native INa was similar to the recombinant NaV1.6 current co-expressed with β1-subunits. The current-voltage (I-V) relationships of native INa were similar to those of recombinant NaV1.6 currents co-expressed with β1-subunits. Application of 4,9-anhydroTTX inhibited the peak amplitude of native INa (K i = 510 nM), recombinant INa (K i = 112 nM), and recombinant INa co-expressed with β1-subunits (K i = 92 nM). The half-maximal (Vhalf) activation and inactivation of native INa values were similar to those observed in recombinant INa co-expressed with β1-subunits. These results suggest that β1-subunit proteins are likely to be expressed mainly in the smooth muscle layers of murine vas deferens and that 4,9-anhydroTTX inhibited not only native INa but also recombinant INa and recombinant INa co-expressed with β1-subunits in a concentration-dependent manner.