Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Rahel Florian; Florian Kraft; Elsa Leitão; Sabine Kaya; Stephan Klebe; Eloi Magnin; Anne-Fleur van Rootselaar; Julien Buratti; Theresa Kühnel; Christopher Schröder; Sebastian Giesselmann; Nikolai Tschernoster; Janine Altmueller; Anaide Lamiral; Boris Keren; Caroline Nava; Delphine Bouteiller; Sylvie Forlani; Ludmila Jornea; Regina Kubica; Tao Ye; Damien Plassard; Bernard Jost; Vincent Meyer; Jean-François Deleuze; Yannick Delpu; Mario Avarello; Lisanne Vijfhuizen; Gabrielle Rudolf; Edouard Hirsch; Thessa Kroes; Philipp Reif; Felix Rosenow; Christos Ganos; Marie Vidailhet; Lionel Thivard; Alexandre Mathieu; Thomas Bourgeron; Ingo Kurth; Haloom Rafehi; Laura Steenpass; Bernhard Horsthemke; Eric Leguern; Karl Martin Klein; Pierre Labauge; Mark Bennett; Melanie Bahlo; Jozef Gecz; Mark Corbett; Marina Tijssen; Arn van den Maagdenberg; Christel Depienne

doi:10.1038/s41467-019-12763-9

Journal articles

Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Rahel Florian ¹ Florian Kraft ² Elsa Leitão ¹ Sabine Kaya ¹ Stephan Klebe ^{3, 4} Eloi Magnin ⁵ Anne-Fleur van Rootselaar ^{6, 7} Julien Buratti ⁸ Theresa Kühnel ¹ Christopher Schröder ¹ Sebastian Giesselmann ² Nikolai Tschernoster ^{9, 10} Janine Altmueller ^{10, 9} Anaide Lamiral ⁵ Boris Keren ⁸ Caroline Nava ^{8, 11} Delphine Bouteiller ¹¹ Sylvie Forlani ¹¹ Ludmila Jornea ¹¹ Regina Kubica ¹ Tao Ye ¹² Damien Plassard ¹² Bernard Jost ¹² Vincent Meyer ^{13, 14} Jean-François Deleuze ^{13, 14} Yannick Delpu ¹⁵ Mario Avarello ¹⁵ Lisanne Vijfhuizen ¹⁶ Gabrielle Rudolf ^{12, 17} Edouard Hirsch ^{18, 17} Thessa Kroes ^{19, 20} Philipp Reif ^{21, 22} Felix Rosenow ^{21, 22} Christos Ganos ²³ Marie Vidailhet ^{11, 24} Lionel Thivard ²⁴ Alexandre Mathieu ²⁵ Thomas Bourgeron ²⁵ Ingo Kurth ² Haloom Rafehi ^{26, 27, 28} Laura Steenpass ¹ Bernhard Horsthemke ¹ Eric Leguern ^{8, 11} Karl Martin Klein ^{21, 22, 29} Pierre Labauge ³⁰ Mark Bennett ^{26, 27, 28} Melanie Bahlo ^{26, 27} Jozef Gecz ^{20, 31} Mark Corbett ²⁰ Marina Tijssen ³² Arn van den Maagdenberg ¹⁶ Christel Depienne ^{1, 11, 12}

1 Institute of Human Genetics - Institut für Humangenetik [Essen]

2 RWTH Aachen University

3 Uniklinik Essen - Universitätsklinikum Essen [Universität Duisburg-Essen]

4 Universität Duisburg-Essen [Essen]

5 Hôpital Jean Minjoz

6 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]

7 Amsterdam Neuroscience [Pays-Bas]

8 Service de génétique [CHU Pitié-Salpêtrière]

9 CMMC - Centre for Molecular Medicine Cologne [Cologne]

10 CCG - Cologne Center for Genomics [Cologne]

11 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

12 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

13 JACOB - Institut de Biologie François JACOB

14 CNG - Centre National de Génotypage

15 genomic vision

16 Leiden University Medical Center (LUMC)

17 CRéER - Centre de référence des épilepsies rares [CHRU Strasbourg]

18 Service de Neurologie [Strasbourg]

19 School of Biological Sciences [Adelaïde]

20 University of Adelaide

21 Goethe-University Frankfurt am Main

22 Philipps University of Marburg

23 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin

24 Département de Neurologie [Paris]

25 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions

26 WEHI - The Walter and Eliza Hall Institute of Medical Research

27 University of Melbourne

28 Epilepsy Research Centre

29 University of Calgary

30 Hôpital Gui de Chauliac

31 SAHMRI - South Australian Health and Medical Research Institute [ Adelaide]

32 UMCG - University Medical Center Groningen [Groningen]

Abstract : Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Keywords : Neurodegenerative diseases Genomic instability Neurological disorders Epilepsy

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Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Life Sciences [q-bio] / Genetics / Human genetics

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Contributor : Alexandre Mathieu <>
Submitted on : Monday, May 4, 2020 - 5:01:33 PM
Last modification on : Wednesday, August 19, 2020 - 11:19:02 AM

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Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

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Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

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