The Experts below are selected from a list of 3159 Experts worldwide ranked by ideXlab platform

Geoffrey W Abbott - One of the best experts on this subject based on the ideXlab platform.

  • KCNQ and KCNE Isoform-Dependent Pharmacology Rationalizes Native American Dual Use of Specific Plants as Both Analgesics and Gastrointestinal Therapeutics
    'Frontiers Media SA', 2021
    Co-Authors: Geoffrey W Abbott, Kaitlyn E. Redford, Ryan F. Yoshimura, Rían W. Manville, Luiz Moreira, Kevin Tran, Grey Arena, Alexandra Kookootsedes, Emma Lasky, Elliot Gunnison
    Abstract:

    Indigenous peoples of the Americas are proficient in botanical medicine. KCNQ family voltage-gated potassium (Kv) channels are sensitive to a variety of ligands, including plant metabolites. Here, we screened methanolic extracts prepared from 40 Californian coastal redwood forest plants for effects on Kv current and membrane potential in Xenopus oocytes heterologously expressing KCNQ2/3, which regulates excitability of neurons, including those that sense pain. Extracts from 9 of the 40 plant species increased KCNQ2/3 current at –60 mV by ≥threefold (maximally, 15-fold by Urtica dioica) and/or hyperpolarized membrane potential by ≥-3 mV (maximally, –11 mV by Arctostaphylos glandulosa). All nine plants have traditionally been used as both analgesics and gastrointestinal therapeutics. Of two extracts tested, both acted as KCNQ-dependent analgesics in mice. KCNQ2/3 activation at physiologically relevant, subthreshold membrane potentials by tannic acid, gallic acid and quercetin provided molecular correlates for analgesic action of several of the plants. While tannic acid also activated KCNQ1 and KCNQ1-KCNE1 at hyperpolarized, negative membrane potentials, it inhibited KCNQ1-KCNE3 at both negative and positive membrane potentials, mechanistically rationalizing historical use of tannic acid-containing plants as gastrointestinal therapeutics. KCNE dependence of KCNQ channel modulation by plant metabolites therefore provides a molecular mechanistic basis for Native American use of specific plants as both analgesics and gastrointestinal aids

  • the KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury
    The FASEB Journal, 2019
    Co-Authors: Leng Zhou, Torsten K Roepke, Clemens Kohncke, Geoffrey W Abbott
    Abstract:

    The KCNE2 single transmembrane-spanning voltage-gated potassium (Kv) channel β subunit is ubiquitously expressed and essential for normal function of a variety of cell types, often via regulation of the KCNQ1 Kv channel. A polymorphism upstream of KCNE2 is associated with reduced lung function in human populations, but the pulmonary consequences of KCNE2 gene disruption are unknown. Here, germline deletion of mouse KCNE2 reduced pulmonary expression of potassium channel α subunits Kcnq1 and Kcnb1 but did not alter expression of other Kcne genes. KCNE2 colocalized and coimmunoprecipitated with Kcnq1 in mouse lungs, suggesting the formation of pulmonary Kcnq1-KCNE2 potassium channel complexes. KCNE2 deletion reduced blood O2, increased CO2, increased pulmonary apoptosis, and increased inflammatory mediators TNF-α, IL-6, and leukocytes in bronchoalveolar lavage (BAL) fluids. Consistent with increased pulmonary vascular leakage, KCNE2 deletion increased plasma, BAL albumin, and the BAL:plasma albumin concentration ratio. KCNE2-/- mouse lungs exhibited baseline induction of the reperfusion injury salvage kinase pathway but were less able to respond via this pathway to imposed pulmonary ischemia/reperfusion injury (IRI). We conclude that KCNE2 regulates KCNQ1 in the lungs and is required for normal lung function and resistance to pulmonary IRI. Our data support a causal relationship between KCNE2 gene disruption and lung dysfunction.-Zhou, L., Kohncke, C., Hu, Z., Roepke, T. K., Abbott, G. W. The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury.

  • Targeted Deletion of KCNE2 Impairs HCN Channel Function in Mouse Thalamocortical Circuits
    2016
    Co-Authors: Shui-wang Ying, Kerry Purtell, Elizabeth C King, Geoffrey W Abbott, Vikram A. K, Peter A. Goldstein
    Abstract:

    Background: Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate the pacemaking current, Ih, which regulates neuronal excitability, burst firing activity, rhythmogenesis, and synaptic integration. The physiological consequence of HCN activation depends on regulation of channel gating by endogenous modulators and stabilization of the channel complex formed by principal and ancillary subunits. KCNE2 is a voltage-gated potassium channel ancillary subunit that also regulates heterologously expressed HCN channels; whether KCNE2 regulates neuronal HCN channel function is unknown. Methodology/Principal Findings: We investigated the effects of KCNE2 gene deletion on Ih properties and excitability in ventrobasal (VB) and cortical layer 6 pyramidal neurons using brain slices prepared from KCNE2+/+ and KCNE22/2 mice. KCNE2 deletion shifted the voltage-dependence of Ih activation to more hyperpolarized potentials, slowed gating kinetics, and decreased Ih density. KCNE2 deletion was associated with a reduction in whole-brain expression of both HCN1 and HCN2 (but not HCN4), although co-immunoprecipitation from whole-brain lysates failed to detect interaction of KCNE2 with HCN1 or 2. KCNE2 deletion also increased input resistance and temporal summation of subthreshold voltage responses; this increased intrinsic excitability enhanced burst firing in response to 4-aminopyridine. Burst duration increased in corticothalamic, but not thalamocortical, neurons, suggesting enhanced cortical excitatory input to the thalamus; suc

  • kcne1 and kcne3 the yin and yang of voltage gated k channel regulation
    Gene, 2016
    Co-Authors: Geoffrey W Abbott
    Abstract:

    Abstract The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE subunits appears to be regulation of voltage-gated potassium (Kv) channels, and the best-understood KCNE complexes are with the KCNQ1 Kv α subunit. Here, we review the often opposite effects of KCNE1 and KCNE3 on Kv channel biology, with an emphasis on regulation of KCNQ1. Slow-activating I Ks channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways. Because of their contrasting effects on KCNQ1 function, KCNE1 and KCNE3 have proved invaluable tools in the mechanistic understanding of how channel gating can be manipulated, and each may also provide a window into novel insights and new therapeutic opportunities in K + channel pharmacology. Finally, findings from studies of Kcne1 −/− and Kcne3 −/− mouse lines serve to illustrate the complexity of KCNE biology and KCNE-linked disease states.

  • kcne1 and kcne3 the yin and yang of voltage gated k channel regulation
    Gene, 2016
    Co-Authors: Geoffrey W Abbott
    Abstract:

    Abstract The human KCNE gene family comprises five genes encoding single transmembrane-spanning ion channel regulatory subunits. The primary function of KCNE subunits appears to be regulation of voltage-gated potassium (Kv) channels, and the best-understood KCNE complexes are with the KCNQ1 Kv α subunit. Here, we review the often opposite effects of KCNE1 and KCNE3 on Kv channel biology, with an emphasis on regulation of KCNQ1. Slow-activating I Ks channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways. Because of their contrasting effects on KCNQ1 function, KCNE1 and KCNE3 have proved invaluable tools in the mechanistic understanding of how channel gating can be manipulated, and each may also provide a window into novel insights and new therapeutic opportunities in K + channel pharmacology. Finally, findings from studies of Kcne1 −/− and Kcne3 −/− mouse lines serve to illustrate the complexity of KCNE biology and KCNE-linked disease states.

Michael J Ackerman - One of the best experts on this subject based on the ideXlab platform.

  • spectrum and prevalence of mutations from the first 2 500 consecutive unrelated patients referred for the familion long qt syndrome genetic test
    Heart Rhythm, 2009
    Co-Authors: Jamie D Kapplinger, David J Tester, Arthur A.m. Wilde, Benjamin A Salisbury, Janet L Carr, Carole Harriskerr, Guido D Pollevick, Michael J Ackerman
    Abstract:

    Background Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation. Objectives Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION ® LQTS clinical genetic test. Methods Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Results Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1 , 159 of 226 in KCNH2 , and 70 of 110 in SCN5A . Conclusion This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.

  • genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing
    Heart Rhythm, 2006
    Co-Authors: David J Tester, Carla M Haglund, Amanda L Farley, Jonathan C Makielski, Melissa L. Will, Puneeta Arya, Michael J Ackerman
    Abstract:

    Background Mutations in the RyR2 -encoded cardiac ryanodine receptor/calcium release channel and in CASQ2 -encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). Objectives The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. Methods Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. Results Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. Conclusion Putative CPVT1-causing mutations in RyR2 were seen in

  • genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing
    Heart Rhythm, 2006
    Co-Authors: David J Tester, Carla M Haglund, Amanda L Farley, Jonathan C Makielski, Melissa L. Will, Puneeta Arya, Michael J Ackerman
    Abstract:

    Background Mutations in the RyR2 -encoded cardiac ryanodine receptor/calcium release channel and in CASQ2 -encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). Objectives The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. Methods Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. Results Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. Conclusion Putative CPVT1-causing mutations in RyR2 were seen in

  • compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long qt syndrome genetic testing
    Heart Rhythm, 2005
    Co-Authors: David J Tester, Carla M Haglund, Melissa L. Will, Michael J Ackerman
    Abstract:

    Objectives The purpose of this study was to determine the spectrum and prevalence of cardiac channel mutations among a large cohort of consecutive, unrelated patients referred for long QT syndrome (LQTS) genetic testing. Background Congenital LQTS is a primary cardiac channelopathy. More than 300 mutations have been identified in five genes encoding key ion channel subunits. Until the recent release of the commercial clinical genetic test, LQTS genetic testing had been performed in research laboratories during the past decade. Methods A cardiac channel gene screen for LQTS-causing mutations in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed for 541 consecutive, unrelated patients (358 females, average age at diagnosis 24 ± 16 years, average QTc 482 ± 57 ms) referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing between August 1997 and July 2004. A comprehensive open reading frame and splice site analysis of the 60 protein-encoding exons was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. Results Overall, 211 putative pathogenic mutations in KCNQ1 (88), KCNH2 (89), SCN5A (32), KCNE1 (1), and KCNE2 (1) were found in 272 unrelated patients (50%). Among the genotype positive patients (N = 272), 243 had single pathogenic mutations (LQT1: n=120 patients; LQT2: n=93; LQT3: n=26; LQT5: n=3; LQT6: n=1), and 29 patients (10% of genotype-positive patients and 5% overall) had two LQTS-causing mutations. The majority of mutations were missense mutations (154/210 [73%]), singletons (identified in only a single unrelated patient: 165/210 [79%]), and novel (125/211 [59%]). None of the mutations identified were seen in more than 1,500 reference alleles. Those patients harboring multiple mutations were younger at diagnosis (15 ± 11 years vs 24 ± 16 years, P =.003). Conclusions In this comprehensive cardiac channel gene screen of the largest cohort of consecutive, unrelated patients referred for LQTS genetic testing, half of the patients had an identifiable mutation. The majority of mutations continue to represent novel singletons that expand the published compendium of LQTS-causing mutations by 35%. These observations should facilitate diagnostic interpretation of the clinical genetic test for LQTS.

  • spectrum and frequency of cardiac channel defects in swimming triggered arrhythmia syndromes
    Circulation, 2004
    Co-Authors: Grace R Choi, Carla M Haglund, David J Tester, Melissa L. Will, Laura J Kopplin, Michael J Ackerman
    Abstract:

    Background— Swimming is a relatively genotype-specific arrhythmogenic trigger for type 1 long-QT syndrome (LQT1). We hypothesize that mimickers of concealed LQT1, namely catecholaminergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac events. Methods and Results— Between August 1997 and May 2003, 388 consecutive, unrelated patients were referred specifically for LQTS genetic testing. The presence of a personal and/or family history of a near-drowning or drowning was determined by review of the medical records and/or phone interviews and was blinded to genetic test results. Comprehensive mutational analysis of the 5 LQTS-causing channel genes, KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), along with KCNJ2 (Andersen-Tawil syndrome) and targeted analysis of 18 CPVT1-associated exons in RyR2, was performed with the use of denaturing high-performance liquid chromatography and direct DNA sequencing. Approximately 11% (43 of 388) of the index ...

David J Tester - One of the best experts on this subject based on the ideXlab platform.

  • spectrum and prevalence of mutations from the first 2 500 consecutive unrelated patients referred for the familion long qt syndrome genetic test
    Heart Rhythm, 2009
    Co-Authors: Jamie D Kapplinger, David J Tester, Arthur A.m. Wilde, Benjamin A Salisbury, Janet L Carr, Carole Harriskerr, Guido D Pollevick, Michael J Ackerman
    Abstract:

    Background Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation. Objectives Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION ® LQTS clinical genetic test. Methods Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6). Results Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1 , 159 of 226 in KCNH2 , and 70 of 110 in SCN5A . Conclusion This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.

  • genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing
    Heart Rhythm, 2006
    Co-Authors: David J Tester, Carla M Haglund, Amanda L Farley, Jonathan C Makielski, Melissa L. Will, Puneeta Arya, Michael J Ackerman
    Abstract:

    Background Mutations in the RyR2 -encoded cardiac ryanodine receptor/calcium release channel and in CASQ2 -encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). Objectives The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. Methods Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. Results Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. Conclusion Putative CPVT1-causing mutations in RyR2 were seen in

  • genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing
    Heart Rhythm, 2006
    Co-Authors: David J Tester, Carla M Haglund, Amanda L Farley, Jonathan C Makielski, Melissa L. Will, Puneeta Arya, Michael J Ackerman
    Abstract:

    Background Mutations in the RyR2 -encoded cardiac ryanodine receptor/calcium release channel and in CASQ2 -encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). Objectives The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. Methods Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. Results Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. Conclusion Putative CPVT1-causing mutations in RyR2 were seen in

  • compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long qt syndrome genetic testing
    Heart Rhythm, 2005
    Co-Authors: David J Tester, Carla M Haglund, Melissa L. Will, Michael J Ackerman
    Abstract:

    Objectives The purpose of this study was to determine the spectrum and prevalence of cardiac channel mutations among a large cohort of consecutive, unrelated patients referred for long QT syndrome (LQTS) genetic testing. Background Congenital LQTS is a primary cardiac channelopathy. More than 300 mutations have been identified in five genes encoding key ion channel subunits. Until the recent release of the commercial clinical genetic test, LQTS genetic testing had been performed in research laboratories during the past decade. Methods A cardiac channel gene screen for LQTS-causing mutations in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed for 541 consecutive, unrelated patients (358 females, average age at diagnosis 24 ± 16 years, average QTc 482 ± 57 ms) referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing between August 1997 and July 2004. A comprehensive open reading frame and splice site analysis of the 60 protein-encoding exons was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. Results Overall, 211 putative pathogenic mutations in KCNQ1 (88), KCNH2 (89), SCN5A (32), KCNE1 (1), and KCNE2 (1) were found in 272 unrelated patients (50%). Among the genotype positive patients (N = 272), 243 had single pathogenic mutations (LQT1: n=120 patients; LQT2: n=93; LQT3: n=26; LQT5: n=3; LQT6: n=1), and 29 patients (10% of genotype-positive patients and 5% overall) had two LQTS-causing mutations. The majority of mutations were missense mutations (154/210 [73%]), singletons (identified in only a single unrelated patient: 165/210 [79%]), and novel (125/211 [59%]). None of the mutations identified were seen in more than 1,500 reference alleles. Those patients harboring multiple mutations were younger at diagnosis (15 ± 11 years vs 24 ± 16 years, P =.003). Conclusions In this comprehensive cardiac channel gene screen of the largest cohort of consecutive, unrelated patients referred for LQTS genetic testing, half of the patients had an identifiable mutation. The majority of mutations continue to represent novel singletons that expand the published compendium of LQTS-causing mutations by 35%. These observations should facilitate diagnostic interpretation of the clinical genetic test for LQTS.

  • spectrum and frequency of cardiac channel defects in swimming triggered arrhythmia syndromes
    Circulation, 2004
    Co-Authors: Grace R Choi, Carla M Haglund, David J Tester, Melissa L. Will, Laura J Kopplin, Michael J Ackerman
    Abstract:

    Background— Swimming is a relatively genotype-specific arrhythmogenic trigger for type 1 long-QT syndrome (LQT1). We hypothesize that mimickers of concealed LQT1, namely catecholaminergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac events. Methods and Results— Between August 1997 and May 2003, 388 consecutive, unrelated patients were referred specifically for LQTS genetic testing. The presence of a personal and/or family history of a near-drowning or drowning was determined by review of the medical records and/or phone interviews and was blinded to genetic test results. Comprehensive mutational analysis of the 5 LQTS-causing channel genes, KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), along with KCNJ2 (Andersen-Tawil syndrome) and targeted analysis of 18 CPVT1-associated exons in RyR2, was performed with the use of denaturing high-performance liquid chromatography and direct DNA sequencing. Approximately 11% (43 of 388) of the index ...

Alfred L George - One of the best experts on this subject based on the ideXlab platform.

  • Allelic Complexity in Long QT Syndrome: A Family-Case Study
    'MDPI AG', 2017
    Co-Authors: Alberto Zullo, Carlos G. Vanoye, Alfred L George, Giulia Frisso, Nicola Detta, Berardo Sarubbi, Emanuele Romeo, Angela Cordella, Raffaele Calabrò, Francesco Salvatore
    Abstract:

    Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers

  • structural underpinnings for modulation of the voltage gated potassium channel kcnq1 by the kcne family of proteins
    Biophysical Journal, 2010
    Co-Authors: Wade D Van Horn, Congbao Kang, Carlos G. Vanoye, Alfred L George, R Welch, Charles R Sanders
    Abstract:

    The voltage-gated potassium channel KCNQ1 is modulated by KCNE1 to form the IKs current involved in cardiac repolarization. KCNE1 is the best characterized member of a family of modulatory proteins which impart distinct ion channel physiology. Mutations in KCNQ1 and familial KCNE proteins have been linked to human diseases including congenital deafness and congenital long QT syndrome, which is an inherited predisposition to potentially life-threatening cardiac arrhythmias. The biophysical basis of the KCNE1 modulation of KCNQ1 has been previously characterized in our lab with an interdisciplinary approach utilizing nuclear magnetic resonance (NMR) spectroscopy, electrophysiology, biochemistry, and computational biology. In this work we extend the characterization to include two other family members; namely, KCNE3 and KCNE4. KCNQ1 homology models and the KCNE family proteins KCNE1, KCNE3, and KCNE4 are used as the basis of a comparative study to deduce the molecular mechanisms of voltage-gated potassium channel regulation by these accessory subunits. KCNE1 binds to KCNQ1 and causes delayed channel activation and increased conductance, while, KCNE3 promotes rapid and increased conductance in KCNQ1. On the other hand, KCNE4 binding causes a strict inhibition of KCNQ1 conductance. In this work we present data that suggests the structural biological basis for how the homologous KCNE1, KCNE3, and KCNE4 proteins modulate KCNQ1 in such starkly contrasting manners. This work was supported by NIH grant R01DC007416.

  • kcne4 can co associate with the iks kcnq1 kcne1 channel complex
    FEBS Journal, 2008
    Co-Authors: Lauren J Manderfield, Alfred L George
    Abstract:

    : Voltage-gated potassium (K(V)) channels can form heteromultimeric complexes with a variety of accessory subunits, including KCNE proteins. Heterologous expression studies have demonstrated diverse functional effects of KCNE subunits on several K(V) channels, including KCNQ1 (K(V)7.1) that, together with KCNE1, generates the slow-delayed rectifier current (I(Ks)) important for cardiac repolarization. In particular, KCNE4 exerts a strong inhibitory effect on KCNQ1 and other K(V) channels, raising the possibility that this accessory subunit is an important potassium current modulator. A polyclonal KCNE4 antibody was developed to determine the human tissue expression pattern and to investigate the biochemical associations of this protein with KCNQ1. We found that KCNE4 is widely and variably expressed in several human tissues, with greatest abundance in brain, liver and testis. In heterologous expression experiments, immunoprecipitation followed by immunoblotting was used to establish that KCNE4 directly associates with KCNQ1, and can co-associate together with KCNE1 in the same KCNQ1 complex to form a 'triple subunit' complex (KCNE1-KCNQ1-KCNE4). We also used cell surface biotinylation to demonstrate that KCNE4 does not impair plasma membrane expression of either KCNQ1 or the triple subunit complex, indicating that biophysical mechanisms probably underlie the inhibitory effects of KCNE4. The observation that multiple KCNE proteins can co-associate with and modulate KCNQ1 channels to produce biochemically diverse channel complexes has important implications for understanding K(V) channel regulation in human physiology.

  • prevalence of long qt syndrome gene variants in sudden infant death syndrome
    Circulation, 2007
    Co-Authors: Marianne Arnestad, Lia Crotti, Torleiv O Rognum, Roberto Insolia, Matteo Pedrazzini, Chiara Ferrandi, Ashild Vege, Dao W Wang, Troy E Rhodes, Alfred L George
    Abstract:

    Background— The hypothesis that some cases of sudden infant death syndrome (SIDS) could be caused by long-QT syndrome (LQTS) has been supported by molecular studies. However, there are inadequate data regarding the true prevalence of mutations in arrhythmia-susceptibility genes among SIDS cases. Given the importance and potential implications of these observations, we performed a study to more accurately quantify the contribution to SIDS of LQTS gene mutations and rare variants. Methods and Results— Molecular screening of 7 genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, CAV3) associated with LQTS was performed with denaturing high-performance liquid chromatography and nucleotide sequencing of genomic DNA from 201 cases diagnosed as SIDS according to the Nordic Criteria, and from 182 infant and adult controls. All SIDS and control cases originated from the same regions in Norway. Genetic analysis was blinded to diagnosis. Mutations and rare variants were found in 26 of 201 cases (12.9%). On the basis of ...

Torsten K Roepke - One of the best experts on this subject based on the ideXlab platform.

  • the KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury
    The FASEB Journal, 2019
    Co-Authors: Leng Zhou, Torsten K Roepke, Clemens Kohncke, Geoffrey W Abbott
    Abstract:

    The KCNE2 single transmembrane-spanning voltage-gated potassium (Kv) channel β subunit is ubiquitously expressed and essential for normal function of a variety of cell types, often via regulation of the KCNQ1 Kv channel. A polymorphism upstream of KCNE2 is associated with reduced lung function in human populations, but the pulmonary consequences of KCNE2 gene disruption are unknown. Here, germline deletion of mouse KCNE2 reduced pulmonary expression of potassium channel α subunits Kcnq1 and Kcnb1 but did not alter expression of other Kcne genes. KCNE2 colocalized and coimmunoprecipitated with Kcnq1 in mouse lungs, suggesting the formation of pulmonary Kcnq1-KCNE2 potassium channel complexes. KCNE2 deletion reduced blood O2, increased CO2, increased pulmonary apoptosis, and increased inflammatory mediators TNF-α, IL-6, and leukocytes in bronchoalveolar lavage (BAL) fluids. Consistent with increased pulmonary vascular leakage, KCNE2 deletion increased plasma, BAL albumin, and the BAL:plasma albumin concentration ratio. KCNE2-/- mouse lungs exhibited baseline induction of the reperfusion injury salvage kinase pathway but were less able to respond via this pathway to imposed pulmonary ischemia/reperfusion injury (IRI). We conclude that KCNE2 regulates KCNQ1 in the lungs and is required for normal lung function and resistance to pulmonary IRI. Our data support a causal relationship between KCNE2 gene disruption and lung dysfunction.-Zhou, L., Kohncke, C., Hu, Z., Roepke, T. K., Abbott, G. W. The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia and reperfusion injury.

  • effects of kcne subunit deletion on polarized trafficking of the kcnq1 potassium channel in vivo
    Biophysical Journal, 2010
    Co-Authors: Geoffrey W Abbott, Kerry Purtell, Elizabeth C King, Gianina Panaghie, Daniel Lerner, Torsten K Roepke
    Abstract:

    The KCNQ1 potassium channel alpha subunit generates essential K+ currents in human heart and in a range of polarized secretory epithelia. The polarity of KCNQ1 trafficking varies between different epithelia, but neither the importance nor the mechanism for this polarity are well understood. KCNQ1 co-localizes apically with the KCNE2 beta subunit in gastric parietal cells but basolaterally with KCNE3 in colonic crypts. Both KCNE2 and KCNE3 convert KCNQ1 to a constitutively active channel. Here, genetic deletion of KCNE2 in mice resulted in 5-fold upregulation of Kcne3, formation of Kcnq1-Kcne3 complexes, and basolateral Kcnq1 targeting in parietal cells, and gastritis cystica profunda stemming from achlorhydria and earlier hyperplasia. In contrast, KCNE2-/-Kcne3-/- mice exhibited apical parietal cell Kcnq1 localization. Thus, in parietal cells, apical Kcnq1 localization is required for gastric acid secretion, and the apical localization per se does not require KCNE2. Kcne3, if present, actively targets Kcnq1 basolaterally, ultimately causing a preneoplastic condition which in humans could predispose to gastric cancer.View Large Image | View Hi-Res Image | Download PowerPoint Slide

  • the KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion
    Journal of Biological Chemistry, 2006
    Co-Authors: Torsten K Roepke, Philipp Kirchhoff, Jeffrey B Young, Daniel J Lerner, John P. Geibel, Stephanie M Busque, Arun Anantharam, Geoffrey W Abbott
    Abstract:

    Abstract Genes in the KCNE family encode single transmembrane domain ancillary subunits that co-assemble with voltage-gated potassium (Kv) channel α subunits to alter their function. KCNE2 (also known as MiRP1) is expressed in the heart, is associated with human cardiac arrhythmia, and modulates cardiac Kv α subunits hERG and KCNQ1 in vitro. KCNE2 and KCNQ1 are also expressed in parietal cells, leading to speculation they form a native channel complex there. Here, we disrupted the murine KCNE2 gene and found that KCNE2 (-/-) mice have a severe gastric phenotype with profoundly reduced parietal cell proton secretion, abnormal parietal cell morphology, achlorhydria, hypergastrinemia, and striking gastric glandular hyperplasia arising from an increase in the number of non-acid secretory cells. KCNQ1 exhibited abnormal distribution in gastric glands from KCNE2 (-/-) mice, with increased expression in non-acid secretory cells. Parietal cells from KCNE2 (+/-) mice exhibited normal architecture but reduced proton secretion, and KCNE2 (+/-) mice were hypochlorhydric, indicating a gene-dose effect and a primary defect in gastric acid secretion. These data demonstrate that KCNE2 is essential for gastric acid secretion, the first genetic evidence that a member of the KCNE gene family is required for normal gastrointestinal function.