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Michael J. Ackerman - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the KCND3 encoded kv4 3 k channel associated with autopsy negative sudden unexplained death
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (<1.0%) and two SUDS cases (1.6%) harbored potentially pathogenic mutations in KCND3. The novel p.Val392Ile, p.Ser530Pro, and p.Gly600Arg mutations involved highly conserved residues and were absent in 1,560 reference alleles. Although the SIDS-associated p.Ser530Pro mutation demonstrated a wild-type (WT) electrophysiological phenotype when heterologously expressed, the SUDS-associated p.Val392Ile and p.Gly600Arg mutations significantly increased peak current density at +40 mV in comparison with WT by 100.4% (P < 0.05) and 50.4% (P < 0.05), respectively. p.Val392Ile also slowed recovery from inactivation 3.6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. Hum Mutat 33:989–997, 2012. © 2012 Wiley Periodicals, Inc.
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Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (
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transient outward current i to gain of function mutations in the KCND3 encoded kv4 3 potassium channel and brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest.
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Transient outward current (I to ) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death–predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V 1 –V 3 . Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3 -encoded Kv4.3 (I to ) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I to ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I to current density by 146.2% (n = 15, P P to maximal conductance associated with the heterozygous expression of either L450F or G600R. Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I to current gradient within the right ventricle where KCND3 expression is the highest.
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abstract 12094 transient outward current ito gain of function mutation g600r in the KCND3 encoded kv4 3 channel and brugada syndrome
Circulation, 2010Co-Authors: John R. Giudicessi, Dan Ye, Chad J. Kritzberger, Richard M Albertson, Michael J. AckermanAbstract:Introduction: Brugada syndrome (BrS) is a sudden death predisposing genetic condition associated so far with mutations in 8 BrS-susceptibility genes and is believed to account for 20% of autopsy negative sudden unexplained death syndrome (SUDS) cases. Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesize that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS and SUDS even though no mutations in the KCND3 —encoded Kv4.3 α-subunit have been described. Methods: KCND3 comprehensive mutational analysis was conducted using PCR, DHPLC, and direct sequencing of DNA derived from 14 unrelated BrS patients (13 males, 36.0 ± 9.3 years, 70% white) and 122 unrelated SUDS cases (75 males, 17.5 ± 12.3 years, 89% white). DNA from 780 healthy individuals was examined to assess allelic frequency for all identified non-synonymous variants. The putative BrS- and SUDS-associated mutation was engineered by site directed mutagenesis and co-expressed with wild-type KChIP2 in HEK293 cells to re-capitulate the I to current. Wild-type and mutant I to currents were recorded using the whole cell patch clamp technique. Results: Both a BrS and SUDS case (2/136, 1.5%) hosted the same novel missense mutation, G600R, absent in > 1500 reference alleles (p 1 -V 3 , spontaneous atrial fibrillation, and a significant paternal family history of sudden death. The G600R-positive SUDS case was a 23-year-old male unexplained drowning victim with no significant past medical history. Both cases were BrS1–8 genotype negative. Co-expression of Kv4.3-G600R plus KChIP2-WT significantly increased I to current density from −20 mV to +40 mV compared to Kv4.3-WT plus KChIP2-WT (n = 14 and 10 for each group, p Conclusions: This study provides the first molecular and functional evidence implicating a KCND3 gain-of-function mutation in the pathogenesis of BrS and SUDS with the potential for a lethal arrhythmia being precipitated by a biogenic increase in I to current.
John R. Giudicessi - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the KCND3 encoded kv4 3 k channel associated with autopsy negative sudden unexplained death
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (<1.0%) and two SUDS cases (1.6%) harbored potentially pathogenic mutations in KCND3. The novel p.Val392Ile, p.Ser530Pro, and p.Gly600Arg mutations involved highly conserved residues and were absent in 1,560 reference alleles. Although the SIDS-associated p.Ser530Pro mutation demonstrated a wild-type (WT) electrophysiological phenotype when heterologously expressed, the SUDS-associated p.Val392Ile and p.Gly600Arg mutations significantly increased peak current density at +40 mV in comparison with WT by 100.4% (P < 0.05) and 50.4% (P < 0.05), respectively. p.Val392Ile also slowed recovery from inactivation 3.6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. Hum Mutat 33:989–997, 2012. © 2012 Wiley Periodicals, Inc.
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Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (
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transient outward current i to gain of function mutations in the KCND3 encoded kv4 3 potassium channel and brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest.
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Transient outward current (I to ) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death–predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V 1 –V 3 . Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3 -encoded Kv4.3 (I to ) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I to ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I to current density by 146.2% (n = 15, P P to maximal conductance associated with the heterozygous expression of either L450F or G600R. Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I to current gradient within the right ventricle where KCND3 expression is the highest.
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abstract 12094 transient outward current ito gain of function mutation g600r in the KCND3 encoded kv4 3 channel and brugada syndrome
Circulation, 2010Co-Authors: John R. Giudicessi, Dan Ye, Chad J. Kritzberger, Richard M Albertson, Michael J. AckermanAbstract:Introduction: Brugada syndrome (BrS) is a sudden death predisposing genetic condition associated so far with mutations in 8 BrS-susceptibility genes and is believed to account for 20% of autopsy negative sudden unexplained death syndrome (SUDS) cases. Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesize that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS and SUDS even though no mutations in the KCND3 —encoded Kv4.3 α-subunit have been described. Methods: KCND3 comprehensive mutational analysis was conducted using PCR, DHPLC, and direct sequencing of DNA derived from 14 unrelated BrS patients (13 males, 36.0 ± 9.3 years, 70% white) and 122 unrelated SUDS cases (75 males, 17.5 ± 12.3 years, 89% white). DNA from 780 healthy individuals was examined to assess allelic frequency for all identified non-synonymous variants. The putative BrS- and SUDS-associated mutation was engineered by site directed mutagenesis and co-expressed with wild-type KChIP2 in HEK293 cells to re-capitulate the I to current. Wild-type and mutant I to currents were recorded using the whole cell patch clamp technique. Results: Both a BrS and SUDS case (2/136, 1.5%) hosted the same novel missense mutation, G600R, absent in > 1500 reference alleles (p 1 -V 3 , spontaneous atrial fibrillation, and a significant paternal family history of sudden death. The G600R-positive SUDS case was a 23-year-old male unexplained drowning victim with no significant past medical history. Both cases were BrS1–8 genotype negative. Co-expression of Kv4.3-G600R plus KChIP2-WT significantly increased I to current density from −20 mV to +40 mV compared to Kv4.3-WT plus KChIP2-WT (n = 14 and 10 for each group, p Conclusions: This study provides the first molecular and functional evidence implicating a KCND3 gain-of-function mutation in the pathogenesis of BrS and SUDS with the potential for a lethal arrhythmia being precipitated by a biogenic increase in I to current.
Charles Antzelevitch - One of the best experts on this subject based on the ideXlab platform.
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Inter-Regulation of Kv4.3 and Voltage-Gated Sodium Channels Underlies Predisposition to Cardiac and Neuronal Channelopathies
International Journal of Molecular Sciences, 2020Co-Authors: Jérôme Clatot, Nathalie Neyroud, Charlotte Souil, Jing Huang, Pascale Guicheney, Charles AntzelevitchAbstract:Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that Kv4.3 and Nav variants regulate each other’s function, thus modulating INa/Ito balance in cardiomyocytes and INa/I(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Nav1.5 and Kv4.3 channels in HEK293 cells. INa and Ito were recorded. Results: SCN5A variants associated with BrS reduced INa, but increased Ito. Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of Ito, significantly reduced INa, whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of Ito significantly increased INa. Auxiliary subunits Navβ1, MiRP3 and KChIP2 also modulated INa/Ito balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF SCN5A variants can increase Kv4.3 cell-surface expression. Conclusion: Nav and Kv4.3 channels modulate each other’s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.
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A Genetic Variant in DPP10 Linked to Inherited J-Wave Syndrome Associated with Sudden Cardiac Death by Augmentation of Kv4.3 Channel Current
Heart Rhythm, 2012Co-Authors: Hector Barajas-martinez, Ryan Pfeiffer, Andy Powers, Timothy K. Knilans, Dan Hu, Elena Burashnikov, Charles AntzelevitchAbstract:Background Mutations in genes encoding the α ( KCND3 ) and β ( KCNE3 ) subunits of genes encoding the cardiac transient outward potassium (I to ) have been associated with inherited cardiac arrhythmia syndromes such as Brugada syndrome (BrS) and sudden infant death syndromes (SIDS). Here, we identify and characterize a novel genetic variant in DPP10 associated with severe pediatric J-wave syndrome (JWS) characterized by early repolarization syndrome (ERS). Methods and Results The proband, a 14-year-old female, presented with atrial fibrillation. At age 16 she developed accentuated J waves in all ECG leads and multiple episodes of polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF; type 3 ERS), resulting in appropriate ICD shocks. Cilostazol proved effective in quieting VT/VF. She died of an electrical storm at age 21. Genetic screening using Next Gen and Sanger methods uncovered a genetic variant in DPP10 but no variants in any other JWS susceptibility genes. Transversion of thymine for guanine at nucleotide 15 predicted substitution of aspartic acid (D) for glutamine acid (E) at position 5 in exon 1b in the N-terminal of DPP10 . The variation was present in 5 of 448 ethnically matched healthy controls (1.1%). E5 is highly conserved among species. The E5D rare polymorphism was found in the proband's aunt who was asymptomatic but displayed ER pattern in select ECG leads. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques at 37°C. Coexpression of KCND3 + KChIP2 + DPP10 /E5D generated Kv4.3 current density (I to ) 169.9% and 70.6% greater compared with KCND3 + KChIP2 + DPP10 /WT when homozygously and heterozygously expressed, respectively (n = 9–12, P to and recovery from inactivation was slower in E5D channels. Quinidine (5 μM) and cilostazol (5 μM) inhibited I to by approximately 50% at +20 mV in E5D channels but less so (20 %) in WT channels. Conclusions Our results provide, for the first time, evidence supporting the hypothesis that DDP10 is a novel susceptibility gene for life-threatening arrhythmias associated with ERS. Our data suggest that DPP10- E5D contributes to generation of a pathogenic substrate by boosting I to and that quinidine and cilostazol serve as therapeutic options in this setting by reducing I to .
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novel mutations in the KCND3 encoded kv4 3 k channel associated with autopsy negative sudden unexplained death
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (<1.0%) and two SUDS cases (1.6%) harbored potentially pathogenic mutations in KCND3. The novel p.Val392Ile, p.Ser530Pro, and p.Gly600Arg mutations involved highly conserved residues and were absent in 1,560 reference alleles. Although the SIDS-associated p.Ser530Pro mutation demonstrated a wild-type (WT) electrophysiological phenotype when heterologously expressed, the SUDS-associated p.Val392Ile and p.Gly600Arg mutations significantly increased peak current density at +40 mV in comparison with WT by 100.4% (P < 0.05) and 50.4% (P < 0.05), respectively. p.Val392Ile also slowed recovery from inactivation 3.6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. Hum Mutat 33:989–997, 2012. © 2012 Wiley Periodicals, Inc.
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Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (
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transient outward current i to gain of function mutations in the KCND3 encoded kv4 3 potassium channel and brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest.
Dan Ye - One of the best experts on this subject based on the ideXlab platform.
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novel mutations in the KCND3 encoded kv4 3 k channel associated with autopsy negative sudden unexplained death
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (<1.0%) and two SUDS cases (1.6%) harbored potentially pathogenic mutations in KCND3. The novel p.Val392Ile, p.Ser530Pro, and p.Gly600Arg mutations involved highly conserved residues and were absent in 1,560 reference alleles. Although the SIDS-associated p.Ser530Pro mutation demonstrated a wild-type (WT) electrophysiological phenotype when heterologously expressed, the SUDS-associated p.Val392Ile and p.Gly600Arg mutations significantly increased peak current density at +40 mV in comparison with WT by 100.4% (P < 0.05) and 50.4% (P < 0.05), respectively. p.Val392Ile also slowed recovery from inactivation 3.6-fold, indicating a mixed electrophysiological phenotype. This is the first report indicating that KCND3 may serve as a rare genetic substrate in the pathogenesis of SUDS but not SIDS cases. Hum Mutat 33:989–997, 2012. © 2012 Wiley Periodicals, Inc.
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Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death.
Human Mutation, 2012Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Chad J. Kritzberger, Vladislav V. Nesterenko, David J. Tester, Michael J. AckermanAbstract:Heritable arrhythmia syndromes, including Brugada syndrome (BrS) and idiopathic ventricular fibrillation (IVF), may serve as the pathogenic basis for autopsy-negative sudden unexplained death (SUD) and sudden infant death syndrome (SIDS). Emerging evidence has linked perturbations in the transient outward current (Ito) conducted by the KCND3-encoded Kv4.3 pore-forming α-subunit to BrS or IVF. However, the contribution of KCND3 mutations to autopsy-negative SUD/SIDS is unknown. To investigate the potential association between KCND3 and SUD/SIDS, mutational analysis of KCND3 was conducted in 123 SUDS and 292 SIDS victims using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct sequencing. Overall, one SIDS case (
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transient outward current i to gain of function mutations in the KCND3 encoded kv4 3 potassium channel and brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest.
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Transient outward current (I to ) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome
Heart Rhythm, 2011Co-Authors: John R. Giudicessi, Charles Antzelevitch, Dan Ye, Vladislav V. Nesterenko, David J. Tester, Lia Crotti, Alessandra Mugione, Richard M Albertson, Peter J Schwartz, Michael J. AckermanAbstract:Background Brugada syndrome (BrS) is a sudden death–predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V 1 –V 3 . Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS. Methods Comprehensive mutational analysis of KCND3 -encoded Kv4.3 (I to ) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I to ion currents were recorded using whole-cell patch clamp. Results Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I to current density by 146.2% (n = 15, P P to maximal conductance associated with the heterozygous expression of either L450F or G600R. Conclusions These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I to current gradient within the right ventricle where KCND3 expression is the highest.
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abstract 12094 transient outward current ito gain of function mutation g600r in the KCND3 encoded kv4 3 channel and brugada syndrome
Circulation, 2010Co-Authors: John R. Giudicessi, Dan Ye, Chad J. Kritzberger, Richard M Albertson, Michael J. AckermanAbstract:Introduction: Brugada syndrome (BrS) is a sudden death predisposing genetic condition associated so far with mutations in 8 BrS-susceptibility genes and is believed to account for 20% of autopsy negative sudden unexplained death syndrome (SUDS) cases. Given the prominent role of the transient outward current (I to ) in BrS pathogenesis, we hypothesize that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS and SUDS even though no mutations in the KCND3 —encoded Kv4.3 α-subunit have been described. Methods: KCND3 comprehensive mutational analysis was conducted using PCR, DHPLC, and direct sequencing of DNA derived from 14 unrelated BrS patients (13 males, 36.0 ± 9.3 years, 70% white) and 122 unrelated SUDS cases (75 males, 17.5 ± 12.3 years, 89% white). DNA from 780 healthy individuals was examined to assess allelic frequency for all identified non-synonymous variants. The putative BrS- and SUDS-associated mutation was engineered by site directed mutagenesis and co-expressed with wild-type KChIP2 in HEK293 cells to re-capitulate the I to current. Wild-type and mutant I to currents were recorded using the whole cell patch clamp technique. Results: Both a BrS and SUDS case (2/136, 1.5%) hosted the same novel missense mutation, G600R, absent in > 1500 reference alleles (p 1 -V 3 , spontaneous atrial fibrillation, and a significant paternal family history of sudden death. The G600R-positive SUDS case was a 23-year-old male unexplained drowning victim with no significant past medical history. Both cases were BrS1–8 genotype negative. Co-expression of Kv4.3-G600R plus KChIP2-WT significantly increased I to current density from −20 mV to +40 mV compared to Kv4.3-WT plus KChIP2-WT (n = 14 and 10 for each group, p Conclusions: This study provides the first molecular and functional evidence implicating a KCND3 gain-of-function mutation in the pathogenesis of BrS and SUDS with the potential for a lethal arrhythmia being precipitated by a biogenic increase in I to current.
Morten S Olesen - One of the best experts on this subject based on the ideXlab platform.
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Clinical Research Sodium Current and Potassium Transient Outward Current Genes in Brugada Syndrome: Screening and Bioinformatics
2020Co-Authors: Anders G. Holst, Stig Haunso, Henrik Jensen, Jesper Hastrup Svendsen, Siamak Saber, Massoud Houshmand, E. V. Zaklyazminskaya, Yinman Wang, Lena Refsgaard, 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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gain of function mutations in potassium channel subunit kcne2 associated with early onset lone atrial fibrillation
Biomarkers in Medicine, 2014Co-Authors: Jonas B Nielsen, Morten S Olesen, Jenspeter David, Stig Haunso, Bo Hjorth Bentzen, Søren-peter Olesen, Jesper Hastrup Svendsen, Nicole SchmittAbstract:Aims: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Disturbances in cardiac potassium conductance are considered as one of the disease mechanisms in AF. We aimed to investigate if mutations in potassium-channel β-subunits KCNE2 and KCNE3 are associated with early-onset lone AF. Methods & results: The coding regions of KCNE2 and KCNE3 were bidirectionally sequenced in 192 unrelated patients diagnosed with early-onset lone AF (<40 years). Two nonsynonymous missense mutations were identified in KCNE2 (M23L and I57T). Both mutations were absent in a healthy control group (n = 1500 alleles). Electrophysiological investigations were performed for both mutations in combination with candidate pore-forming α-subunits KV7.1, KV11.1, KV4.3 and KV1.5. A significant gain-of-function effect was observed upon coexpression with KV7.1 and KV7.1 + KCNE1. Confocal imaging found no differences in subcellular localization. No disease-suspected mutations were identified in KCNE3. Conclusion: We identified two...
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a novel KCND3 gain of function mutation associated with early onset of persistent lone atrial fibrillation
Cardiovascular Research, 2013Co-Authors: Morten S Olesen, Anders G. Holst, Lena Refsgaard, Anders Peter Larsen, Soren Grubb, Stig HaunsoAbstract:Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia, and early-onset lone AF has been linked to mutations in genes encoding ion channels. Mutations in the pore forming subunit KV4.3 leading to an increase in the transient outward potassium current ( I to) have previously been associated with the Brugada Syndrome. Here we aim to determine if mutations in KV4.3 or in the auxiliary subunit K+ Channel-Interacting Protein (KChIP) 2 are associated with early-onset lone AF. Methods and results Two hundred and nine unrelated early-onset lone AF patients (<40 years) were recruited. The entire coding sequence of KCND3 and KCNIP2 was bidirectionally sequenced. One novel non-synonymous mutation A545P was found in KCND3 and was neither present in the control group ( n = 432 alleles) nor in any publicly available database. The proband had onset of persistent AF at the age of 22, and no mutations in genes previously associated with AF were found. Electrophysiological analysis of KV4.3-A545P expressed in CHO-K1 cells, revealed that peak-current density was increased and the onset of inactivation was slower compared with WT, resulting in a significant gain-of-function both in the absence and the presence of KChIP2. Conclusion Gain-of-function mutations in KV4.3 have previously been described in Brugada Syndrome, however, this is the first report of a KV4.3 gain-of-function mutation in early-onset lone AF. This association of KV4.3 gain-of-function and early-onset lone AF further supports the hypothesis that increased potassium current enhances AF susceptibility.
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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, Henrik Jensen, Jesper Hastrup Svendsen, Siamak Saber, Massoud Houshmand, E. V. Zaklyazminskaya, Yinman Wang, Lena Refsgaard, 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.