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Licensed Unlicensed Requires Authentication Published by De Gruyter March 24, 2022

Genetics meets function in sodium channel-related pain disorders

  • Jannis Körner

    Dr. Jannis Körner, MD, is a clinical scientist in the Department of Physiology and Anesthesiology in the Medical Faculty of the RWTH Aachen University Hospital. After completing his medical studies in Aachen and Lausanne he completed his MD thesis at the Institute of Physiology in Aachen and the Institute of complex Systems in Jülich investigating the mechanobiology of sodium channels. His research focuses on 1) the classification of neuronal sub identities in sensory neurons and the identification of biomarkers of neuropathic pain related neuron classes and 2) structural and functional studies of sodium channel biophysics.

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    , Natja Haag

    Dr. Natja Haag, PhD, is a Postdoc/starting Group leader in the Institute for Human Genetics at RWTH Aachen University, Germany. She is a Co-PI within the Sodium Channel Network Aachen (SCNAachen) aiming to identify novel NaV channel variants as well as novel genes implicated in monogenic pain disorders. Her research is focused on 1) the genetics and pathomechanisms of inherited pain disorders and 2) the modelling of rare neurodevelopmental and neurodegenerative diseases using mouse models and patient-derived iPSCs.

    , Ingo Kurth

    Prof. Ingo Kurth, MD, is Head of the Institute of Human Genetics and Head of the Genomics Core Unit at the University Hospital RWTH Aachen, Germany. Before moving to Aachen, he was appointed Heisenberg Professor for Molecular Neurogenetics by the German Research Foundation (DFG). His group uses next-generation sequencing technologies to identify new causes of inherited neuropathies and understand the underlying disease mechanisms. He coordinates a European network for inherited sensory neuropathies and pain insensitivity (ENISNIP).

    and Angelika Lampert

    Prof. Angelika Lampert, MD, is a full professor in the Institute of Physiology (Neurophysiology) at the RWTH Aachen University, Germany. Following her medical studies in Jena she worked as a postdoc at Yale University. In Aachen she is now the coordinator of the Sodium Channel Network Aachen (SCNAachen). Her research concentrates on translational pain research: 1) biophysics and structure-function relation of voltage-gated sodium channels and 2) induced pluripotent stem cell (iPS-cell) derived human peripheral sensory neurons as a disease model system.

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From the journal Neuroforum

Abstract

Voltage-gated sodium channels are crucial for pain perception. This is illustrated by several human genetic conditions that lead to either chronic pain or, vice versa, to congenital painlessness. The type of mutation, its impact on neuron excitability as well as the affected sodium channel subtype delineates a complex picture of the disorders. Genetic variants in sodium channels may affect the complex biophysical gating and also their trafficking, association with other proteins and more complex regulations of the channel protein and function, thus allowing us to explore the subtle but impactful effects of their dysregulation for human nociception. A detailed understanding of these pain disorders provides a unique chance to understand the detailed intricacies of nociception and pathological conditions such as neuropathic pain. With increasing awareness of the importance of sodium channel variants in neuropathic pain, more patients are genetically screened, sometimes identifying variants of unclear significance (VUS). Bioinformatic tools help to assess their potential disease causing impact, but functional studies using patch-clamp experiments in cell lines are needed to allow for reliable conclusions. Often cell lines are not sufficient to show a physiologically relevant phenotype and more complex, time intensive models, such as induced pluripotent stem cells (iPS-cells) are employed. A challenge remains to identify the role of each sodium channel VUS in the context of the detailed cellular genetic and functional context. To lay the grounds for such a detailed interpretation, we need a correlation of cellular function and genetic transcription on a single cell basis, as it is possible with the Patch-Seq technique. The more detailed our knowledge becomes on functional and genetic sensory neurons subtypes and their role in the generation of neuropathic pain, the more targeted the personal or population-based treatment can be.

Zusammenfassung

Spannungsgesteuerte Natriumkanäle sind entscheidend für die Schmerzwahrnehmung. Dies wird durch mehrere humangenetische Erkrankungen veranschaulicht, die entweder zu chronischen Schmerzen oder umgekehrt zu angeborener Schmerzlosigkeit führen. Die Art der Mutation, ihr Einfluss auf die Erregbarkeit von Neuronen sowie der betroffene Natriumkanal-Subtyp zeichnen ein komplexes Bild der Erkrankungen. Genetische Varianten in Natriumkanälen können viel mehr als ihr biophysikalisches Schaltverhalten beeinflussen, was die Komplexität der menschlichen Nozizeption weiter unterstreicht. Ein detailliertes Verständnis dieser monogenetischen Schmerzstörungen erlaubt es in besonderer Weise, die Feinheiten der Nozizeption und ihrer Pathophysiologie, wie z. B. im Falle neuropathischer Schmerzen zu verstehen. Mit zunehmendem Bewusstsein für die Bedeutung von Natriumkanalvarianten bei neuropathischen Schmerzen werden immer mehr Patient*innen genetisch untersucht und neben klar pathogenen Varianten auch Varianten unklarer Signifikanz (VUS) identifiziert. Bioinformatische Vorhersageprogramme und Vorhersagen zur Häufigkeit einer Veränderung helfen bei der Einschätzung ihrer Krankheitsursächlichkeit, oft lässt aber nur die Untersuchung ihrer funktionellen Auswirkung, bspw. durch Patch-Clamp-Experimente in Zelllinien, zuverlässige Schlussfolgerungen zu. Oft sind für ein umfassendes Verständnis genetischer Varianten aber auch komplexere und zeitintensivere Modelle wie induzierte pluripotente Stammzellen notwendig. Es bleibt eine Herausforderung, die Rolle jeder VUS in einem Natriumkanal durch detaillierte zelluläre und genetische Modelle zu untersuchen. Die Korrelation zwischen Zellfunktion und Transkription auf Einzelzellbasis, wie sie mit der Patch-Seq-Technik möglich ist, trägt weiter zum Verständnis genetischer Varianten bei. Je detaillierter unser Wissen über funktionelle und genetische sensorische Neuronen-Subtypen und ihre Rolle bei der Entstehung von neuropathischen Schmerzen wird, desto zielgerichteter kann die individuelle oder allgemeingültige Schmerztherapie erfolgen.


Corresponding author: Angelika Lampert, Institute of Physiology, Uniklinik RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany, E-mail:

Award Identifier / Grant number: LA 2740/3–1

Award Identifier / Grant number: 363055819/GRK2415

Award Identifier / Grant number: 368482240/GRK2416

Award Identifier / Grant number: KU 1587/6-1

Award Identifier / Grant number: IZKF TN1-1/IA 532001

Award Identifier / Grant number: IZKF TN1-2/IA 532002

Award Identifier / Grant number: 13GW0334B

Award Identifier / Grant number: 825575

About the authors

Jannis Körner

Dr. Jannis Körner, MD, is a clinical scientist in the Department of Physiology and Anesthesiology in the Medical Faculty of the RWTH Aachen University Hospital. After completing his medical studies in Aachen and Lausanne he completed his MD thesis at the Institute of Physiology in Aachen and the Institute of complex Systems in Jülich investigating the mechanobiology of sodium channels. His research focuses on 1) the classification of neuronal sub identities in sensory neurons and the identification of biomarkers of neuropathic pain related neuron classes and 2) structural and functional studies of sodium channel biophysics.

Natja Haag

Dr. Natja Haag, PhD, is a Postdoc/starting Group leader in the Institute for Human Genetics at RWTH Aachen University, Germany. She is a Co-PI within the Sodium Channel Network Aachen (SCNAachen) aiming to identify novel NaV channel variants as well as novel genes implicated in monogenic pain disorders. Her research is focused on 1) the genetics and pathomechanisms of inherited pain disorders and 2) the modelling of rare neurodevelopmental and neurodegenerative diseases using mouse models and patient-derived iPSCs.

Ingo Kurth

Prof. Ingo Kurth, MD, is Head of the Institute of Human Genetics and Head of the Genomics Core Unit at the University Hospital RWTH Aachen, Germany. Before moving to Aachen, he was appointed Heisenberg Professor for Molecular Neurogenetics by the German Research Foundation (DFG). His group uses next-generation sequencing technologies to identify new causes of inherited neuropathies and understand the underlying disease mechanisms. He coordinates a European network for inherited sensory neuropathies and pain insensitivity (ENISNIP).

Angelika Lampert

Prof. Angelika Lampert, MD, is a full professor in the Institute of Physiology (Neurophysiology) at the RWTH Aachen University, Germany. Following her medical studies in Jena she worked as a postdoc at Yale University. In Aachen she is now the coordinator of the Sodium Channel Network Aachen (SCNAachen). Her research concentrates on translational pain research: 1) biophysics and structure-function relation of voltage-gated sodium channels and 2) induced pluripotent stem cell (iPS-cell) derived human peripheral sensory neurons as a disease model system.

  1. Author contributions: All authors wrote and revised the manuscript.

  2. Research funding: This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation LA 2740/3–1, 363055819/GRK2415 Mechanobiology of 3D epithelial tissues (ME3T); 368482240/GRK2416, MultiSenses-MultiScales), by a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF TN1-1/IA 532001 and IZKF TN1-2/IA 532002) and by the BMBF consortium “Bio2Treat” (German Federal Ministry of Education and Research/Bundesministerium für Bildung und Forschung, BMBF, “Chronische Schmerzen – Innovative medizintechnische Lösungen zur Verbesserung von Prävention, Diagnostik und Therapie,” contract number 13GW0334B). The “European Network on Inherited Sensory Neuropathies and Insensitivity to Pain (ENISNIP) is supported by the Deutsche Forschungsgemeinschaft (DFG) (KU 1587/6-1) under the frame of EJP RD, the European Joint Programme on Rare Diseases. In addition, the ENISNIP project has received funding from the European Union’s Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP N° 825575.

  3. Conflict of interest statement: The authors have no conflicts of interest to declare. AL has a research contract with Hoffmann-La Roche and Grünenthal and receives consulting fees from Grünenthal, which do not affect the work presented here.

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Published Online: 2022-03-24
Published in Print: 2022-05-25

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