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Lori L Isom - One of the best experts on this subject based on the ideXlab platform.
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Excitatory and inhibitory neuron defects in a mouse model of SCN1B-linked EIEE52
Annals of clinical and translational neurology, 2020Co-Authors: Jacob M Hull, Chunling Chen, Luis F. Lopez-santiago, Heather A. O'malley, Alexandra A. Bouza, Yukun Yuan, Nicholas Denomme, Charles Anumonwo, Lori L IsomAbstract:Objective Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked to DEEs. While these VGSC-linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that Scn2a-, Scn3a-, and Scn8a-linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (INa ) and pyramidal neuron hyperexcitability. In contrast, Scn1a-linked DEE variants, in general, are loss-of-function, resulting in decreased INa and hypoexcitability of fast-spiking interneurons. VGSC β1 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology. Methods We investigated excitability defects in pyramidal and parvalbumin-positive (PV +) interneurons in the SCN1B-/- model of EIEE52. We also used SCN1BFL/FL mice to delete SCN1B in specific neuronal populations. Results SCN1B-/- cortical PV + interneurons were hypoexcitable, with reduced INa density. SCN1B-/- cortical pyramidal neurons had population-specific changes in excitability and impaired INa density. SCN1B deletion in PV + neurons resulted in 100% lethality, whereas deletion in Emx1 + or Camk2a + neurons did not affect survival. Interpretation This work suggests that SCN1B-linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.
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SCN1B deletion in adult mice results in seizures and SUDEP.
Annals of clinical and translational neurology, 2019Co-Authors: Heather A. O'malley, Chunling Chen, Jacob M Hull, Brittany C. Clawson, Gic Owens‐fiestan, Margaret B. Jameson, Sara J. Aton, Jack M. Parent, Lori L IsomAbstract:Pathogenic loss-of-function variants in SCN1B are linked to Dravet syndrome (DS). Previous work suggested that neuronal pathfinding defects underlie epileptogenesis and SUDEP in the SCN1B null mouse model of DS. We tested this hypothesis by inducing SCN1B deletion in adult mice that had developed normally. Epilepsy and SUDEP, which occur by postnatal day 21 in SCN1B null animals, were observed within 20 days of induced SCN1B deletion in adult mice, suggesting that epileptogenesis in SCN1B-DS does not result from defective brain development. Thus, the developmental brain defects observed previously in SCN1B null mice may model other co-morbidities of DS.
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delayed maturation of gabaergic signaling in the scn1a and SCN1B mouse models of dravet syndrome
Scientific Reports, 2019Co-Authors: Yukun Yuan, Alexandra A. Bouza, Heather A Omalley, Melissa A Smaldino, Jacob M Hull, Lori L IsomAbstract:Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy characterized by severe, pharmacoresistant seizures and the highest risk of Sudden Unexpected Death in Epilepsy (SUDEP) of all epilepsy syndromes. Here, we investigated the time course of maturation of neuronal GABAergic signaling in the SCN1B−/− and Scn1a+/− mouse models of DS. We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABAA-evoked currents compared to wildtype in the third postnatal week. Treatment of SCN1B−/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B- and SCN1A-linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.
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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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β1-C121W Is Down But Not Out: Epilepsy-Associated SCN1B-C121W Results in a Deleterious Gain-of-Function
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016Co-Authors: Larisa C. Kruger, Heather A. O'malley, Jacob M Hull, Amanda Kleeman, Gustavo Patino, Lori L IsomAbstract:Voltage-gated sodium channel (VGSC) β subunits signal through multiple pathways on multiple time scales. In addition to modulating sodium and potassium currents, β subunits play nonconducting roles as cell adhesion molecules, which allow them to function in cell–cell communication, neuronal migration, neurite outgrowth, neuronal pathfinding, and axonal fasciculation. Mutations in SCN1B, encoding VGSC β1 and β1B, are associated with epilepsy. Autosomal-dominant SCN1B-C121W, the first epilepsy-associated VGSC mutation identified, results in genetic epilepsy with febrile seizures plus (GEFS+). This mutation has been shown to disrupt both the sodium-current-modulatory and cell-adhesive functions of β1 subunits expressed in heterologous systems. The goal of this study was to compare mice heterozygous for SCN1B-C121W (SCN1B+/W) with mice heterozygous for the SCN1B-null allele (SCN1B+/−) to determine whether the C121W mutation results in loss-of-function in vivo. We found that SCN1B+/W mice were more susceptible than SCN1B+/− and SCN1B+/+ mice to hyperthermia-induced convulsions, a model of pediatric febrile seizures. β1-C121W subunits are expressed at the neuronal cell surface in vivo. However, despite this, β1-C121W polypeptides are incompletely glycosylated and do not associate with VGSC α subunits in the brain. β1-C121W subcellular localization is restricted to neuronal cell bodies and is not detected at axon initial segments in the cortex or cerebellum or at optic nerve nodes of Ranvier of SCN1BW/W mice. These data, together with our previous results showing that β1-C121W cannot participate in trans-homophilic cell adhesion, lead to the hypothesis that SCN1B-C121W confers a deleterious gain-of-function in human GEFS+ patients. SIGNIFICANCE STATEMENT The mechanisms underlying genetic epilepsy syndromes are poorly understood. Closing this gap in knowledge is essential to the development of new medicines to treat epilepsy. We have used mouse models to understand the mechanism of a mutation in the sodium channel gene SCN1B linked to genetic epilepsy with febrile seizures plus. We report that sodium channel β1 subunit proteins encoded by this mutant gene are expressed at the surface of neuronal cell bodies; however, they do not associate with the ion channel complex nor are they transported to areas of the axon that are critical for proper neuronal firing. We conclude that this disease-causing mutation is not simply a loss-of-function, but instead results in a deleterious gain-of-function in the brain.
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.
Chunling Chen - One of the best experts on this subject based on the ideXlab platform.
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Excitatory and inhibitory neuron defects in a mouse model of SCN1B-linked EIEE52
Annals of clinical and translational neurology, 2020Co-Authors: Jacob M Hull, Chunling Chen, Luis F. Lopez-santiago, Heather A. O'malley, Alexandra A. Bouza, Yukun Yuan, Nicholas Denomme, Charles Anumonwo, Lori L IsomAbstract:Objective Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked to DEEs. While these VGSC-linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that Scn2a-, Scn3a-, and Scn8a-linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (INa ) and pyramidal neuron hyperexcitability. In contrast, Scn1a-linked DEE variants, in general, are loss-of-function, resulting in decreased INa and hypoexcitability of fast-spiking interneurons. VGSC β1 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology. Methods We investigated excitability defects in pyramidal and parvalbumin-positive (PV +) interneurons in the SCN1B-/- model of EIEE52. We also used SCN1BFL/FL mice to delete SCN1B in specific neuronal populations. Results SCN1B-/- cortical PV + interneurons were hypoexcitable, with reduced INa density. SCN1B-/- cortical pyramidal neurons had population-specific changes in excitability and impaired INa density. SCN1B deletion in PV + neurons resulted in 100% lethality, whereas deletion in Emx1 + or Camk2a + neurons did not affect survival. Interpretation This work suggests that SCN1B-linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.
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SCN1B deletion in adult mice results in seizures and SUDEP.
Annals of clinical and translational neurology, 2019Co-Authors: Heather A. O'malley, Chunling Chen, Jacob M Hull, Brittany C. Clawson, Gic Owens‐fiestan, Margaret B. Jameson, Sara J. Aton, Jack M. Parent, Lori L IsomAbstract:Pathogenic loss-of-function variants in SCN1B are linked to Dravet syndrome (DS). Previous work suggested that neuronal pathfinding defects underlie epileptogenesis and SUDEP in the SCN1B null mouse model of DS. We tested this hypothesis by inducing SCN1B deletion in adult mice that had developed normally. Epilepsy and SUDEP, which occur by postnatal day 21 in SCN1B null animals, were observed within 20 days of induced SCN1B deletion in adult mice, suggesting that epileptogenesis in SCN1B-DS does not result from defective brain development. Thus, the developmental brain defects observed previously in SCN1B null mice may model other co-morbidities of DS.
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na channel SCN1B gene regulates dorsal root ganglion nociceptor excitability in vivo
Journal of Biological Chemistry, 2011Co-Authors: Luis F Lopezsantiago, William J. Brackenbury, Chunling Chen, Lori L IsomAbstract:Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by SCN1B. SCN1B null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of SCN1B deletion on CNS neurons have been described. In contrast, little is known about the role of SCN1B in peripheral neurons in vivo. Here we demonstrate that SCN1B null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared with their WT littermates. Investigation of action potential firing shows that SCN1B null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that SCN1B regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK.
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Na+ Channel SCN1B Gene Regulates Dorsal Root Ganglion Nociceptor Excitability in Vivo
The Journal of biological chemistry, 2011Co-Authors: Luis F. Lopez-santiago, Chunling Chen, William J. Brackenbury, Lori L IsomAbstract:Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by SCN1B. SCN1B null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of SCN1B deletion on CNS neurons have been described. In contrast, little is known about the role of SCN1B in peripheral neurons in vivo. Here we demonstrate that SCN1B null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared with their WT littermates. Investigation of action potential firing shows that SCN1B null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that SCN1B regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK.
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A Functional Null Mutation of SCN1B in a Patient with Dravet Syndrome
Journal of Neuroscience, 2009Co-Authors: Gustavo A. Patino, Haruko Miyazaki, Chunling Chen, Luis F. Lopez-santiago, L Claes, Emily A. Slat, Raja S R Dondeti, Heather A. O'malley, Charles B.b. Gray, Nobuyuki NukinaAbstract:Dravet syndrome (also called severe myoclonic epilepsy of infancy) is one of the most severe forms of childhood epilepsy. Most patients have heterozygous mutations in SCN1A, encoding voltage-gated sodium channel Na(v)1.1 alpha subunits. Sodium channels are modulated by beta1 subunits, encoded by SCN1B, a gene also linked to epilepsy. Here we report the first patient with Dravet syndrome associated with a recessive mutation in SCN1B (p.R125C). Biochemical characterization of p.R125C in a heterologous system demonstrated little to no cell surface expression despite normal total cellular expression. This occurred regardless of coexpression of Na(v)1.1 alpha subunits. Because the patient was homozygous for the mutation, these data suggest a functional SCN1B null phenotype. To understand the consequences of the lack of beta1 cell surface expression in vivo, hippocampal slice recordings were performed in SCN1B(-/-) versus SCN1B(+/+) mice. SCN1B(-/-) CA3 neurons fired evoked action potentials with a significantly higher peak voltage and significantly greater amplitude compared with wild type. However, in contrast to the Scn1a(+/-) model of Dravet syndrome, we found no measurable differences in sodium current density in acutely dissociated CA3 hippocampal neurons. Whereas SCN1B(-/-) mice seize spontaneously, the seizure susceptibility of SCN1B(+/-) mice was similar to wild type, suggesting that, like the parents of this patient, one functional SCN1B allele is sufficient for normal control of electrical excitability. We conclude that SCN1B p.R125C is an autosomal recessive cause of Dravet syndrome through functional gene inactivation.