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  1. AU="Carlos G. Vanoye"
  2. AU=Lohrmann Jens
  3. AU="Petersen, Moritz"
  4. AU="Giovanni, L."
  5. AU="Liu, Xingzheng"
  6. AU="Głód, Mateusz"
  7. AU=Teo Kelvin Yi Chong
  8. AU="Khatmi, Aysan"
  9. AU="Erculiani, M"
  10. AU="Olivier Lortholary"
  11. AU="Lisnic, Vanda Juranic"
  12. AU="Seabloom, Eric W"
  13. AU="Odvina, Clarita V"
  14. AU="Singh, Inderbir"
  15. AU="Wonoh Lee"
  16. AU="Nelson, Warrick"
  17. AU="Douglas, David N"
  18. AU="King, Gary"
  19. AU="Barbera, Lauren"
  20. AU="Carlino, Antonio"
  21. AU="Shan, Qing-Hua"
  22. AU="Starko, S"
  23. AU="Lievre, Loïc"
  24. AU=Cammack N
  25. AU="Xia, Qin"
  26. AU="Ong, Ju Lynn"
  27. AU="Cullin, Christophe"
  28. AU="Georg K.S. Andersson"
  29. AU="Jeannel, Gaël-François"
  30. AU="Stuart Woods"
  31. AU="Shchegolev, A."
  32. AU="Nadeau, Pierre-Louis"
  33. AU="Gordon, David E A"
  34. AU="Shahid Mahmood"
  35. AU="Rosenblatt, Karin"
  36. AU="Dasgupta, Suvankar"
  37. AU=Nguyen Sylvain AU=Nguyen Sylvain

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  1. Artikel ; Online: Predicting the functional impact of KCNQ1 variants with artificial neural networks.

    Saksham Phul / Georg Kuenze / Carlos G Vanoye / Charles R Sanders / Alfred L George / Jens Meiler

    PLoS Computational Biology, Vol 18, Iss 4, p e

    2022  Band 1010038

    Abstract: Recent advances in experimental and computational protein structure determination have provided access to high-quality structures for most human proteins and mutants thereof. However, linking changes in structure in protein mutants to functional impact ... ...

    Abstract Recent advances in experimental and computational protein structure determination have provided access to high-quality structures for most human proteins and mutants thereof. However, linking changes in structure in protein mutants to functional impact remains an active area of method development. If successful, such methods can ultimately assist physicians in taking appropriate treatment decisions. This work presents three artificial neural network (ANN)-based predictive models that classify four key functional parameters of KCNQ1 variants as normal or dysfunctional using PSSM-based evolutionary and/or biophysical descriptors. Recent advances in predicting protein structure and variant properties with artificial intelligence (AI) rely heavily on the availability of evolutionary features and thus fail to directly assess the biophysical underpinnings of a change in structure and/or function. The central goal of this work was to develop an ANN model based on structure and physiochemical properties of KCNQ1 potassium channels that performs comparably or better than algorithms using only on PSSM-based evolutionary features. These biophysical features highlight the structure-function relationships that govern protein stability, function, and regulation. The input sensitivity algorithm incorporates the roles of hydrophobicity, polarizability, and functional densities on key functional parameters of the KCNQ1 channel. Inclusion of the biophysical features outperforms exclusive use of PSSM-based evolutionary features in predicting activation voltage dependence and deactivation time. As AI is increasingly applied to problems in biology, biophysical understanding will be critical with respect to 'explainable AI', i.e., understanding the relation of sequence, structure, and function of proteins. Our model is available at www.kcnq1predict.org.
    Schlagwörter Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 006
    Sprache Englisch
    Erscheinungsdatum 2022-04-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  2. Artikel ; Online: Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome

    Kathryn R. Brewer / Georg Kuenze / Carlos G. Vanoye / Alfred L. George / Jens Meiler / Charles R. Sanders

    Frontiers in Pharmacology, Vol

    2020  Band 11

    Abstract: The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (Kv) channels KCNQ1 and hERG as ... ...

    Abstract The cardiac action potential is critical to the production of a synchronized heartbeat. This electrical impulse is governed by the intricate activity of cardiac ion channels, among them the cardiac voltage-gated potassium (Kv) channels KCNQ1 and hERG as well as the voltage-gated sodium (Nav) channel encoded by SCN5A. Each channel performs a highly distinct function, despite sharing a common topology and structural components. These three channels are also the primary proteins mutated in congenital long QT syndrome (LQTS), a genetic condition that predisposes to cardiac arrhythmia and sudden cardiac death due to impaired repolarization of the action potential and has a particular proclivity for reentrant ventricular arrhythmias. Recent cryo-electron microscopy structures of human KCNQ1 and hERG, along with the rat homolog of SCN5A and other mammalian sodium channels, provide atomic-level insight into the structure and function of these proteins that advance our understanding of their distinct functions in the cardiac action potential, as well as the molecular basis of LQTS. In this review, the gating, regulation, LQTS mechanisms, and pharmacological properties of KCNQ1, hERG, and SCN5A are discussed in light of these recent structural findings.
    Schlagwörter cardiac action potential ; long QT syndrome ; KCNQ1 ; hERG ; SCN5A ; structural biology ; Therapeutics. Pharmacology ; RM1-950
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2020-05-01T00:00:00Z
    Verlag Frontiers Media S.A.
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  3. Artikel ; Online: High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity

    Carlos G. Vanoye / Reshma R. Desai / Zhigang Ji / Sneha Adusumilli / Nirvani Jairam / Nora Ghabra / Nishtha Joshi / Eryn Fitch / Katherine L. Helbig / Dianalee McKnight / Amanda S. Lindy / Fanggeng Zou / Ingo Helbig / Edward C. Cooper / Alfred L. George Jr.

    JCI Insight, Vol 7, Iss

    2022  Band 5

    Abstract: Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation ... ...

    Abstract Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
    Schlagwörter Genetics ; Neuroscience ; Medicine ; R
    Thema/Rubrik (Code) 616
    Sprache Englisch
    Erscheinungsdatum 2022-03-01T00:00:00Z
    Verlag American Society for Clinical investigation
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  4. Artikel ; Online: Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation

    Georg Kuenze / Carlos G Vanoye / Reshma R Desai / Sneha Adusumilli / Kathryn R Brewer / Hope Woods / Eli F McDonald / Charles R Sanders / Alfred L George Jr / Jens Meiler

    eLife, Vol

    2020  Band 9

    Abstract: The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action ...

    Abstract The function of the voltage-gated KCNQ1 potassium channel is regulated by co-assembly with KCNE auxiliary subunits. KCNQ1-KCNE1 channels generate the slow delayed rectifier current, IKs, which contributes to the repolarization phase of the cardiac action potential. A three amino acid motif (F57-T58-L59, FTL) in KCNE1 is essential for slow activation of KCNQ1-KCNE1 channels. However, how this motif interacts with KCNQ1 to control its function is unknown. Combining computational modeling with electrophysiological studies, we developed structural models of the KCNQ1-KCNE1 complex that suggest how KCNE1 controls KCNQ1 activation. The FTL motif binds at a cleft between the voltage-sensing and pore domains and appears to affect the channel gate by an allosteric mechanism. Comparison with the KCNQ1-KCNE3 channel structure suggests a common transmembrane-binding mode for different KCNEs and illuminates how specific differences in the interaction of their triplet motifs determine the profound differences in KCNQ1 functional modulation by KCNE1 versus KCNE3.
    Schlagwörter KCNQ1 ; KCNE1 ; long QT syndrome ; voltage-gated potassium ion channel ; Rosetta ; molecular dynamics simulation ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2020-10-01T00:00:00Z
    Verlag eLife Sciences Publications Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  5. Artikel ; Online: Upgraded molecular models of the human KCNQ1 potassium channel.

    Georg Kuenze / Amanda M Duran / Hope Woods / Kathryn R Brewer / Eli Fritz McDonald / Carlos G Vanoye / Alfred L George / Charles R Sanders / Jens Meiler

    PLoS ONE, Vol 14, Iss 9, p e

    2019  Band 0220415

    Abstract: The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) ...

    Abstract The voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and various resting voltage sensor structures. Using molecular dynamics (MD) simulations, the capacity of the models to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor-pore domain interactions were validated. Rosetta energy calculations were applied to assess the utility of each model in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 experimentally characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants exhibited no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural basis for KCNQ1 function and can be used to generate hypotheses to explain KCNQ1 dysfunction.
    Schlagwörter Medicine ; R ; Science ; Q
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2019-01-01T00:00:00Z
    Verlag Public Library of Science (PLoS)
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  6. Artikel ; Online: Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy

    Dina Simkin / Kelly A Marshall / Carlos G Vanoye / Reshma R Desai / Bernabe I Bustos / Brandon N Piyevsky / Juan A Ortega / Marc Forrest / Gabriella L Robertson / Peter Penzes / Linda C Laux / Steven J Lubbe / John J Millichap / Alfred L George Jr / Evangelos Kiskinis

    eLife, Vol

    2021  Band 10

    Abstract: Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition ... ...

    Abstract Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.
    Schlagwörter KCNQ2 ; epileptic encephalopathy ; M-current ; dyshomeostatic ; homeostatic plasticity ; disease modeling ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2021-02-01T00:00:00Z
    Verlag eLife Sciences Publications Ltd
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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  7. Artikel ; Online: Allelic Complexity in Long QT Syndrome

    Alberto Zullo / Giulia Frisso / Nicola Detta / Berardo Sarubbi / Emanuele Romeo / Angela Cordella / Carlos G. Vanoye / Raffaele Calabrò / Alfred L. George / Francesco Salvatore

    International Journal of Molecular Sciences, Vol 18, Iss 8, p

    A Family-Case Study

    2017  Band 1633

    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 ... ...

    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.
    Schlagwörter long-QT syndrome ; cardiac arrhythmias ; potassium channels ; electrophysiology ; KCNQ1 ; KCNH2 ; HERG ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Thema/Rubrik (Code) 572
    Sprache Englisch
    Erscheinungsdatum 2017-07-01T00:00:00Z
    Verlag MDPI AG
    Dokumenttyp Artikel ; Online
    Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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