22 results on '"Soka M"'
Search Results
2. DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.
- Author
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Johnson, R, Otway, R, Chin, E, Horvat, C, Ohanian, M, Wilcox, JAL, Su, Z, Prestes, P, Smolnikov, A, Soka, M, Guo, G, Rath, E, Chakravorty, S, Chrzanowski, L, Hayward, CS, Keogh, AM, Macdonald, PS, Giannoulatou, E, Chang, ACY, Oates, EC, Charchar, F, Seidman, JG, Seidman, CE, Hegde, M, Fatkin, D, Johnson, R, Otway, R, Chin, E, Horvat, C, Ohanian, M, Wilcox, JAL, Su, Z, Prestes, P, Smolnikov, A, Soka, M, Guo, G, Rath, E, Chakravorty, S, Chrzanowski, L, Hayward, CS, Keogh, AM, Macdonald, PS, Giannoulatou, E, Chang, ACY, Oates, EC, Charchar, F, Seidman, JG, Seidman, CE, Hegde, M, and Fatkin, D
- Abstract
BACKGROUND: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. METHODS: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. RESULTS: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. CONCLUSIONS: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.
- Published
- 2023
3. Investigating the Role of Genes and the Environment in Heart Failure With Preserved Ejection Fraction
- Author
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Gorrie, N., Johnson, R., Ohanian, M., Soka, M., Bart, N., and Fatkin, D.
- Published
- 2024
- Full Text
- View/download PDF
4. Genetic and Echocardiographic Determinants of Atrial Fibrillation in Athletes
- Author
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Spencer, L., Janssens, K., Mitchell, A., Ohanian, M., Johnson, R., Soka, M., Young, P., Giannoulatou, E., Lacaze, P., D'Ambrosio, P., Rowe, S., Van Puyvelde, T., Claessens, G., Fatkin, D., and La Gerche, A.
- Published
- 2024
- Full Text
- View/download PDF
5. Analysis of magnetic properties of substituted Li ferrites
- Author
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Slama, J., Gruskova, A., Soka, M., Usakova, M., and Jancarik, V.
- Subjects
Iron alloys -- Magnetic properties ,Iron alloys -- Structure ,Iron alloys -- Thermal properties ,Lithium compounds -- Magnetic properties ,Lithium compounds -- Thermal properties ,Mossbauer spectroscopy -- Usage ,Titanium -- Magnetic properties ,Zinc -- Magnetic properties ,Business ,Electronics ,Electronics and electrical industries - Published
- 2010
6. Analysis of slected Be-substituted NiZn ferrites
- Author
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Slama, J., Usak, E., Soka, M., Gruskova, A., Usakova, M., and Jancarik, V.
- Subjects
Beryllium -- Magnetic properties ,Beryllium -- Electric properties ,Iron compounds -- Magnetic properties ,Iron compounds -- Electric properties ,Mossbauer spectroscopy -- Usage ,Nickel alloys -- Magnetic properties ,Nickel alloys -- Electric properties ,Zinc alloys -- Magnetic properties ,Zinc alloys -- Electric properties ,Business ,Electronics ,Electronics and electrical industries - Published
- 2010
7. Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis
- Author
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Liang, B, Soka, M, Christensen, Alex Horby, Olesen, M, Larsen, Anders Peter, Knop, F K, Wang, Fan, Nielsen, J B, Andersen, M N, Humphreys, David T, Preiss, Thomas, Liang, B, Soka, M, Christensen, Alex Horby, Olesen, M, Larsen, Anders Peter, Knop, F K, Wang, Fan, Nielsen, J B, Andersen, M N, Humphreys, David T, and Preiss, Thomas
- Abstract
The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p<0.001), marked increase in atrial diameter (p<0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electroph
- Published
- 2014
8. Truncating Titin mutations: Are they a primary cause of dilated cardiomyopathy or a susceptibility factor?
- Author
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Johnson, R., primary, Stockhammer, K., additional, Soka, M., additional, Ohanian, M., additional, Lam, L., additional, and Fatkin, D., additional
- Published
- 2014
- Full Text
- View/download PDF
9. In-vivo characterisation and mutation screening of the cardiac two-pore potassium channel, TWIK-1
- Author
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Martin, I., primary, Christensen, A., additional, Soka, M., additional, and Fatkin, D., additional
- Published
- 2014
- Full Text
- View/download PDF
10. TASK-1 potassium channel mutations in atrial fibrillation
- Author
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Olesen, M, Liang, B, Soka, M, Larsen, Anders Peter, Knop, F K, Wang, F, Nielsen, J B, Andersen, M N, Humphreys, David T, Mann, S A, Preiss, Thomas, Fatkin, Diane, Olesen, M, Liang, B, Soka, M, Larsen, Anders Peter, Knop, F K, Wang, F, Nielsen, J B, Andersen, M N, Humphreys, David T, Mann, S A, Preiss, Thomas, and Fatkin, Diane
- Published
- 2013
11. TASK-1 potassium channel mutations in atrial fibrillation
- Author
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Olesen, M., primary, Liang, B., additional, Soka, M., additional, Larsen, A. P., additional, Knop, F. K., additional, Wang, F., additional, Nielsen, J. B., additional, Andersen, M. N., additional, Humphreys, D., additional, Mann, S. A., additional, Vandenberg, J. I., additional, Svendsen, J. H., additional, Haunso, S., additional, Preiss, T., additional, Seebohm, G., additional, Olesen, S.- P., additional, Schmitt, N., additional, and Fatkin, D., additional
- Published
- 2013
- Full Text
- View/download PDF
12. Rare Genetic Variants in Heart Failure with Preserved Ejection Fraction (HFpEF).
- Author
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Gorrie, N., Johnson, R., Ohanian, M., Soka, M., Bart, N., and Fatkin, D.
- Subjects
- *
VENTRICULAR ejection fraction , *HEART failure , *GENETIC variation - Published
- 2024
- Full Text
- View/download PDF
13. Tiered Analysis of Australian Genomics Cardiovascular Genetic Disorders Flagship Genomes Increases the Diagnostic Yield of Genetic Testing.
- Author
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Chang, Y., Rath, E., Singer, E., Trivedi, G., Soka, M., Macciocca, I., Ingles, J., Semsarian, C., McGaughran, J., Fatkin, D., Giannoulatou, E., and Bagnall, R.
- Subjects
- *
GENETIC testing , *CARDIOVASCULAR diseases , *GENETIC disorders , *GENOMICS , *GENOMES - Published
- 2024
- Full Text
- View/download PDF
14. Reduced Ejection Fraction in Elite Endurance Athletes: Clinical and Genetic Overlap With Dilated Cardiomyopathy.
- Author
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Claessen G, De Bosscher R, Janssens K, Young P, Dausin C, Claeys M, Claus P, Goetschalckx K, Bogaert J, Mitchell AM, Flannery MD, Elliott AD, Yu C, Ghekiere O, Robyns T, Van De Heyning CM, Sanders P, Kalman JM, Ohanian M, Soka M, Rath E, Giannoulatou E, Johnson R, Lacaze P, Herbots L, Willems R, Fatkin D, Heidbuchel H, and La Gerche A
- Subjects
- Humans, Male, Female, Adult, Young Adult, Physical Endurance genetics, Adolescent, Genetic Predisposition to Disease, Ventricular Remodeling, Ventricular Function, Left, Cardiomyopathy, Dilated genetics, Cardiomyopathy, Dilated physiopathology, Cardiomyopathy, Dilated diagnostic imaging, Athletes, Stroke Volume
- Abstract
Background: Exercise-induced cardiac remodeling can be profound, resulting in clinical overlap with dilated cardiomyopathy, yet the significance of reduced ejection fraction (EF) in athletes is unclear. The aim is to assess the prevalence, clinical consequences, and genetic predisposition of reduced EF in athletes., Methods: Young endurance athletes were recruited from elite training programs and underwent comprehensive cardiac phenotyping and genetic testing. Those with reduced EF using cardiac magnetic resonance imaging (defined as left ventricular EF <50%, or right ventricular EF <45%, or both) were compared with athletes with normal EF. A validated polygenic risk score for indexed left ventricular end-systolic volume (LVESVi-PRS), previously associated with dilated cardiomyopathy, was assessed. Clinical events were recorded over a mean of 4.4 years., Results: Of the 281 elite endurance athletes (22±8 years, 79.7% male) undergoing comprehensive assessment, 44 of 281 (15.7%) had reduced left ventricular EF (N=12; 4.3%), right ventricular EF (N=14; 5.0%), or both (N=18; 6.4%). Reduced EF was associated with a higher burden of ventricular premature beats (13.6% versus 3.8% with >100 ventricular premature beats/24 h; P =0.008) and lower left ventricular global longitudinal strain (-17%±2% versus -19%±2%; P <0.001). Athletes with reduced EF had a higher mean LVESVi-PRS (0.57±0.13 versus 0.51±0.14; P =0.009) with athletes in the top decile of LVESVi-PRS having an 11-fold increase in the likelihood of reduced EF compared with those in the bottom decile ( P =0.034). Male sex and higher LVESVi-PRS were the only significant predictors of reduced EF in a multivariate analysis that included age and fitness. During follow-up, no athletes developed symptomatic heart failure or arrhythmias. Two athletes died, 1 from trauma and 1 from sudden cardiac death, the latter having a reduced right ventricular EF and a LVESVi-PRS >95%., Conclusions: Reduced EF occurs in approximately 1 in 6 elite endurance athletes and is related to genetic predisposition in addition to exercise training. Genetic and imaging markers may help identify endurance athletes in whom scrutiny about long-term clinical outcomes may be appropriate., Registration: URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374976&isReview=true; Unique identifier: ACTRN12618000716268., Competing Interests: Disclosures None.
- Published
- 2024
- Full Text
- View/download PDF
15. DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies.
- Author
-
Johnson R, Otway R, Chin E, Horvat C, Ohanian M, Wilcox JAL, Su Z, Prestes P, Smolnikov A, Soka M, Guo G, Rath E, Chakravorty S, Chrzanowski L, Hayward CS, Keogh AM, Macdonald PS, Giannoulatou E, Chang ACY, Oates EC, Charchar F, Seidman JG, Seidman CE, Hegde M, and Fatkin D
- Subjects
- Adult, Humans, Male, Female, Comparative Genomic Hybridization, Pedigree, Genotype, Phenotype, Apoptosis Regulatory Proteins genetics, Dystrophin genetics, Adaptor Proteins, Signal Transducing genetics
- Abstract
Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed., Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood., Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN , BAG3 , LMNA , and RBM20 . Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls., Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD -associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management., Competing Interests: Disclosures E. Chin and Dr Hegde are salaried employees of Perkin Elmer Inc. The other authors report no conflicts.
- Published
- 2023
- Full Text
- View/download PDF
16. Polygenic risk scores are associated with atrial electrophysiologic substrate abnormalities and outcomes after atrial fibrillation catheter ablation.
- Author
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Al-Kaisey A, Wong GR, Young P, Chieng D, Hawson J, Anderson R, Sugumar H, Nalliah C, Prabhu M, Johnson R, Soka M, Tarr I, Bakshi A, Yu C, Lacaze P, Giannoulatou E, McLellan A, Lee G, Kistler PM, Fatkin D, and Kalman JM
- Subjects
- Humans, Heart Atria, Cardiac Electrophysiology, Risk Factors, Treatment Outcome, Atrial Fibrillation genetics, Atrial Fibrillation surgery, Catheter Ablation adverse effects
- Published
- 2023
- Full Text
- View/download PDF
17. Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K Ca 1.1, in Sinus Node Function and Arrhythmia Risk.
- Author
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Pineda S, Nikolova-Krstevski V, Leimena C, Atkinson AJ, Altekoester AK, Cox CD, Jacoby A, Huttner IG, Ju YK, Soka M, Ohanian M, Trivedi G, Kalvakuri S, Birker K, Johnson R, Molenaar P, Kuchar D, Allen DG, van Helden DF, Harvey RP, Hill AP, Bodmer R, Vogler G, Dobrzynski H, Ocorr K, and Fatkin D
- Subjects
- Action Potentials drug effects, Animals, Atrial Fibrillation genetics, Atrial Function drug effects, Atrial Function physiology, Embryo, Nonmammalian metabolism, Heart Atria metabolism, Heart Atria pathology, Humans, Indoles chemistry, Indoles metabolism, Indoles pharmacology, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits antagonists & inhibitors, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits metabolism, Mice, Myocardial Contraction, Pedigree, Polymorphism, Genetic, RNA Interference, RNA, Small Interfering metabolism, RNA, Small Interfering pharmacology, Zebrafish, Zebrafish Proteins antagonists & inhibitors, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Atrial Fibrillation pathology, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits genetics, Sinoatrial Node metabolism
- Abstract
Background: KCNMA1 encodes the α-subunit of the large-conductance Ca
2+ -activated K+ channel, KCa 1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa 1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene., Methods: The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of KCa 1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized., Results: A complex KCNMA1 variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of KCa 1.1 in normal hearts using immunostaining and immunogold electron microscopy. KCa 1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the KCa 1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the KCa 1.1 ortholog, kcnma1b , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila KCa 1.1 ortholog, slo , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the KCa 1.1 loss-of-function models., Conclusions: Our data point to a highly conserved role of KCa 1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that KCa 1.1 loss of function may predispose to AF.- Published
- 2021
- Full Text
- View/download PDF
18. Ebola Virus RNA in Semen from an HIV-Positive Survivor of Ebola.
- Author
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Purpura LJ, Rogers E, Baller A, White S, Soka M, Choi MJ, Mahmoud N, Wasunna C, Massaquoi M, Kollie J, Dweh S, Bemah P, Ladele V, Kpaka J, Jawara M, Mugisha M, Subah O, Faikai M, Bailey JA, Rollin P, Marston B, Nyenswah T, Gasasira A, Knust B, Nichol S, and Williams D
- Subjects
- Humans, Male, Middle Aged, RNA, Viral chemistry, Time Factors, Viral Core Proteins chemistry, Viral Matrix Proteins chemistry, Ebolavirus isolation & purification, HIV Infections complications, Hemorrhagic Fever, Ebola virology, RNA, Viral isolation & purification, Semen virology
- Abstract
Ebola virus is known to persist in semen of male survivors of Ebola virus disease (EVD). However, maximum duration of, or risk factors for, virus persistence are unknown. We report an EVD survivor with preexisting HIV infection, whose semen was positive for Ebola virus RNA 565 days after recovery from EVD.
- Published
- 2017
- Full Text
- View/download PDF
19. Implementation of a National Semen Testing and Counseling Program for Male Ebola Survivors - Liberia, 2015-2016.
- Author
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Purpura LJ, Soka M, Baller A, White S, Rogers E, Choi MJ, Mahmoud N, Wasunna C, Massaquoi M, Vanderende K, Kollie J, Dweh S, Bemah P, Christie A, Ladele V, Subah O, Pillai S, Mugisha M, Kpaka J, Nichol S, Ströher U, Abad N, Mettee-Zarecki S, Bailey JA, Rollin P, Marston B, Nyenswah T, Gasasira A, Knust B, and Williams D
- Subjects
- Ebolavirus isolation & purification, Hemorrhagic Fever, Ebola epidemiology, Humans, Liberia epidemiology, Male, Program Development, Semen virology, Counseling organization & administration, Disease Outbreaks prevention & control, Hemorrhagic Fever, Ebola prevention & control, Mass Screening organization & administration, Survivors statistics & numerical data
- Abstract
According to World Health Organization (WHO) data, the Ebola virus disease (Ebola) outbreak that began in West Africa in 2014 has resulted in 28,603 cases and 11,301 deaths (1). In March 2015, epidemiologic investigation and genetic sequencing in Liberia implicated sexual transmission from a male Ebola survivor, with Ebola virus detected by reverse transcription-polymerase chain reaction (RT-PCR) 199 days after symptom onset (2,3), far exceeding the 101 days reported from an earlier Ebola outbreak (4). In response, WHO released interim guidelines recommending that all male survivors, in addition to receiving condoms and sexual risk reduction counseling at discharge from an Ebola treatment unit (ETU), be offered semen testing for Ebola virus RNA by RT-PCR 3 months after disease onset, and every month thereafter until two consecutive semen specimens collected at least 1 week apart test negative for Ebola virus RNA (5). Male Ebola survivors should also receive counseling to promote safe sexual practices until their semen twice tests negative. When these recommendations were released, testing of semen was not widely available in Liberia. Challenges in establishing and operating the first nationwide semen testing and counseling program for male Ebola survivors included securing sufficient resources for the program, managing a public health semen testing program in the context of ongoing research studies that were also collecting and screening semen, identification of adequate numbers of trained counselors and appropriate health communication messages for the program, overcoming Ebola survivor-associated stigma, identification and recruitment of male Ebola survivors, and operation of mobile teams.
- Published
- 2016
- Full Text
- View/download PDF
20. The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size.
- Author
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Christensen AH, Chatelain FC, Huttner IG, Olesen MS, Soka M, Feliciangeli S, Horvat C, Santiago CF, Vandenberg JI, Schmitt N, Olesen SP, Lesage F, and Fatkin D
- Subjects
- Adult, Aged, Animals, Atrial Fibrillation genetics, Atrial Fibrillation metabolism, Atrial Fibrillation pathology, Atrial Fibrillation physiopathology, Female, Gene Expression, Gene Knockout Techniques, Genetic Variation, Heart Atria anatomy & histology, Heart Atria pathology, Humans, Male, Middle Aged, Mutation, Pedigree, Potassium Channels, Tandem Pore Domain deficiency, Potassium Channels, Tandem Pore Domain metabolism, Protein Transport, Risk Factors, Zebrafish, Atrial Remodeling genetics, Genetic Association Studies, Heart Atria metabolism, Heart Rate genetics, Potassium Channels, Tandem Pore Domain genetics
- Abstract
The two-pore domain potassium (K(+)) channel TWIK-1 (or K2P1.1) contributes to background K(+) conductance in diverse cell types. TWIK-1, encoded by the KCNK1 gene, is present in the human heart with robust expression in the atria, however its physiological significance is unknown. To evaluate the cardiac effects of TWIK-1 deficiency, we studied zebrafish embryos after knockdown of the two KCNK1 orthologues, kcnk1a and kcnk1b. Knockdown of kcnk1a or kcnk1b individually caused bradycardia and atrial dilation (p<0.001 vs. controls), while ventricular stroke volume was preserved. Combined knockdown of both kcnk1a and kcnk1b resulted in a more severe phenotype, which was partially reversed by co-injection of wild-type human KCNK1 mRNA, but not by a dominant negative variant of human KCNK1 mRNA. To determine whether genetic variants in KCNK1 might cause atrial fibrillation (AF), we sequenced protein-coding regions in two independent cohorts of patients (373 subjects) and identified three non-synonymous variants, p.R171H, p.I198M and p.G236S, that were all located in highly conserved amino acid residues. In transfected mammalian cells, zebrafish and wild-type human TWIK-1 channels had a similar cellular distribution with predominant localization in the endosomal compartment. Two-electrode voltage-clamp experiments using Xenopus oocytes showed that both zebrafish and wild-type human TWIK-1 channels produced K(+) currents that are sensitive to external K(+) concentration as well as acidic pH. There were no effects of the three KCNK1 variants on cellular localization, current amplitude or reversal potential at pH7.4 or pH6. Our data indicate that TWIK-1 has a highly conserved role in cardiac function and is required for normal heart rate and atrial morphology. Despite the functional importance of TWIK-1 in the atrium, genetic variation in KCNK1 is not a common primary cause of human AF., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
21. Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis.
- Author
-
Liang B, Soka M, Christensen AH, Olesen MS, Larsen AP, Knop FK, Wang F, Nielsen JB, Andersen MN, Humphreys D, Mann SA, Huttner IG, Vandenberg JI, Svendsen JH, Haunsø S, Preiss T, Seebohm G, Olesen SP, Schmitt N, and Fatkin D
- Subjects
- Amino Acid Motifs, Animals, Atrial Fibrillation physiopathology, CHO Cells, Cricetulus, Genetic Predisposition to Disease, Heart Atria anatomy & histology, Heart Atria physiopathology, Humans, Models, Animal, Models, Molecular, Zebrafish, Atrial Fibrillation genetics, Genetic Variation, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Potassium Channels, Tandem Pore Domain genetics, Potassium Channels, Tandem Pore Domain metabolism
- Abstract
The two-pore domain potassium channel, K2P3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p<0.001), marked increase in atrial diameter (p<0.001), and mild increase in end-diastolic ventricular diameter (p=0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on ITASK. Cardiac action potential modeling predicted that reduced ITASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of ITASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
22. Epistatic effects of potassium channel variation on cardiac repolarization and atrial fibrillation risk.
- Author
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Mann SA, Otway R, Guo G, Soka M, Karlsdotter L, Trivedi G, Ohanian M, Zodgekar P, Smith RA, Wouters MA, Subbiah R, Walker B, Kuchar D, Sanders P, Griffiths L, Vandenberg JI, and Fatkin D
- Subjects
- Action Potentials, Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Heart Conduction System physiology, Humans, Male, Middle Aged, Patch-Clamp Techniques, Sequence Analysis, DNA, Young Adult, Atrial Fibrillation genetics, Epistasis, Genetic, Potassium Channels genetics
- Abstract
Objectives: The aim of this study was to evaluate the role of cardiac K(+) channel gene variants in families with atrial fibrillation (AF)., Background: The K(+) channels play a major role in atrial repolarization but single mutations in cardiac K(+) channel genes are infrequently present in AF families. The collective effect of background K(+) channel variants of varying prevalence and effect size on the atrial substrate for AF is largely unexplored., Methods: Genes encoding the major cardiac K(+) channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling was performed using the Courtemanche atrial cell model., Results: Nineteen nonsynonymous variants in 9 genes were found, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K(+) channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K(+) channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization., Conclusions: Families with AF show an excess of rare functional K(+) channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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