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Non-coding repeat expansions associated with familial adult myoclonic epilepsy: a new paradigm of gene-independent monogenic disorders

  • Theresa Kühnel

    Theresa Kühnel studied biology at the Martin-Luther University Halle-Wittenberg specialized in molecular ecology. She then moved into the field of human genetics. She received her Ph.D. in 2020 from the Institute of Human Genetics, University Duisburg-Essen. Since 2021, she is following postdoctoral research work in the group of Prof. Dr. Christel Depienne at the Institute of Human Genetics in Essen.

     ORCID logo EMAIL logo     and Christel Depienne

    Christel Depienne is W2 professor at the Institute of Human Genetics, University Hospital Essen. She studied biology and graduated from the Institute National Agronomique Paris-Grignon (France) in 1996. She received a PhD molecular and cellular biology in 2000 and became assistant professor in human genetics at Pierre & Marie University and Hôpital Pitié Salpêtrière in 2002 with promotion to associate professor in 2008. In 2017, she moved to the University of Essen in Germany where she has been leading research projects aiming to identify new genes and mechanisms involved in neurogenetic disorders.

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Published/Copyright: November 2, 2022
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Neuroforum
From the journal Neuroforum Volume 28 Issue 4

Abstract

Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by cortical myoclonic tremor and seizures. FAME has been mapped to chromosomes (chr) 2, 3, 5 and 8, but the cause has remained elusive for more than a decade. An expansion of intronic TTTTA and TTTCA repeats in SAMD12 was identified as the cause of FAME1 in Japanese families linked to chr 8 in 2018. This discovery triggered the identification of identical repeat expansions at five additional loci (FAME2: STARD7; FAME3: MARCHF6; FAME4: YEATS2; FAME6: TNRC6A and FAME7: RAPGEF2). These genes encode proteins with different functions and subcellular localizations and their expression is unaltered in available peripheral tissues, suggesting that the expansion is pathogenic independently of the gene itself. The pathophysiological mechanisms are not yet known but possibly include toxicity at the RNA level or translation of toxic polypeptides from the repeats, a mechanism known as repeat-associated non-AUG (RAN) translation. FAME is a paradigm of human genetic disorder caused by a non-coding expansion unrelated to the gene where it occurs.

Zusammenfassung

Die familiäre myoklonische Epilepsie bei Erwachsenen (FAME) ist eine seltene autosomal-dominante Störung, die durch kortikalen myoklonischen Tremor und Krampfanfälle gekennzeichnet ist. FAME wurde auf den Chromosomen (Chr) 2, 3, 5 und 8 kartiert, aber die Ursache ist seit mehr als einem Jahrzehnt unklar geblieben. Im Jahr 2018 wurde eine Expansion der intronischen TTTTA-und TTTCA-Wiederholungen in SAMD12 als Ursache von FAME1 in japanischen Familien identifiziert, die mit Chr 8 verbunden sind. Diese Entdeckung löste die Identifizierung identischer Wiederholungsexpansionen an fünf weiteren Loci aus (FAME2: STARD7; FAME3: MARCHF6; FAME4: YEATS2; FAME6: TNRC6A; und FAME7: RAPGEF2). Diese Gene kodieren für Proteine mit unterschiedlichen Funktionen und subzellulären Lokalisierungen, und ihre Expression ist in den verfügbaren peripheren Geweben unverändert, was darauf hindeutet, dass die Expansion unabhängig vom Gen selbst pathogen ist. Die pathophysiologischen Mechanismen sind noch nicht bekannt, umfassen aber möglicherweise eine Toxizität auf RNA-Ebene oder die Translation toxischer Polypeptide aus den Wiederholungen, ein Mechanismus, der als Repeat-associated non-AUG (RAN)-Translation bekannt ist. FAME ist ein Beispiel für eine genetische Störung beim Menschen, die durch eine nicht kodierende Expansion verursacht wird, die nicht mit dem Gen zusammenhängt, in dem sie auftritt.

Keywords: epilepsy; myoclonus/tremor; RAN translation; RNA foci; tandem repeat expansion
Schlüsselwörter: Epilepsie; Myoklonus/Tremor; RAN Translation; RNA Foci; Tandem Repeat Expansion
Corresponding authors: Theresa Kühnel and Christel Depienne, Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany, E-mail: (T. Kühnel), (C. Depienne)

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: 455314768

About the authors

Theresa Kühnel

Theresa Kühnel studied biology at the Martin-Luther University Halle-Wittenberg specialized in molecular ecology. She then moved into the field of human genetics. She received her Ph.D. in 2020 from the Institute of Human Genetics, University Duisburg-Essen. Since 2021, she is following postdoctoral research work in the group of Prof. Dr. Christel Depienne at the Institute of Human Genetics in Essen.

Christel Depienne

Christel Depienne is W2 professor at the Institute of Human Genetics, University Hospital Essen. She studied biology and graduated from the Institute National Agronomique Paris-Grignon (France) in 1996. She received a PhD molecular and cellular biology in 2000 and became assistant professor in human genetics at Pierre & Marie University and Hôpital Pitié Salpêtrière in 2002 with promotion to associate professor in 2008. In 2017, she moved to the University of Essen in Germany where she has been leading research projects aiming to identify new genes and mechanisms involved in neurogenetic disorders.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: Our work was supported by the Deutsche Forschungsgemeinschaft (DFG) – project number 455314768: Dissecting the dynamics and pathological mechanisms associated with TTTCA repeat expansions in Familial Adult Myoclonic Epilepsy.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

  4. Web resources: GnomAD browser: Pathogenic Short Tandem Repeats: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r3. National Center for Biotechnology Information: Ideogram: https://www.ncbi.nlm.nih.gov/genome/tools/gdp. Online Mendelian Inheritance in Man, http://www.omim. org. UniProt consortium: https://www.uniprot.org/.

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Published Online: 2022-11-02
Published in Print: 2022-11-25

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Neuroforum: vom gedruckten Heft ins elektronische Zeitalter
  4. Review articles
  5. The visual representation of space in the primate brain
  6. MicroRNAs in the auditory system: tiny molecules with big impact
  7. Non-coding repeat expansions associated with familial adult myoclonic epilepsy: a new paradigm of gene-independent monogenic disorders
  8. Forebrain development–an intricate balance decides between health and disease
  9. Presentation of scientific institutions
  10. Collaborative Research Centre (CRC 1451) “Key mechanisms of motor control in health and disease”
  11. Collaborative Research Center SFB 1528 “Cognition of Interaction”
  12. SPP2411: ‘Sensing LOOPS: cortico-subcortical interactions for adaptive sensing’
  13. Newly DFG-funded research training group at the University of Kassel: “Biological clocks on multiple time scales” GRK 2749/1
  14. Nachrichten
  15. Catching up in Cologne – 31st Neurobiology Doctoral Students Workshop in Cologne
  16. Nachrichten aus der Gesellschaft
  17. Nachrichten aus der Gesellschaft
https://doi.org/10.1515/nf-2022-0024
Keywords for this article
epilepsy; myoclonus/tremor; RAN translation; RNA foci; tandem repeat expansion

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Neuroforum: vom gedruckten Heft ins elektronische Zeitalter
  4. Review articles
  5. The visual representation of space in the primate brain
  6. MicroRNAs in the auditory system: tiny molecules with big impact
  7. Non-coding repeat expansions associated with familial adult myoclonic epilepsy: a new paradigm of gene-independent monogenic disorders
  8. Forebrain development–an intricate balance decides between health and disease
  9. Presentation of scientific institutions
  10. Collaborative Research Centre (CRC 1451) “Key mechanisms of motor control in health and disease”
  11. Collaborative Research Center SFB 1528 “Cognition of Interaction”
  12. SPP2411: ‘Sensing LOOPS: cortico-subcortical interactions for adaptive sensing’
  13. Newly DFG-funded research training group at the University of Kassel: “Biological clocks on multiple time scales” GRK 2749/1
  14. Nachrichten
  15. Catching up in Cologne – 31st Neurobiology Doctoral Students Workshop in Cologne
  16. Nachrichten aus der Gesellschaft
  17. Nachrichten aus der Gesellschaft
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