Journal article

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

Rahel T Florian, Florian Kraft, Elsa Leitao, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kuehnel, Christopher Schroeder, Sebastian Giesselmann, Nikolai Tschernoster, Janine Altmueller, AnaiDe lamiral, Boris Keren, Caroline Nava, Delphine Bouteiller, Sylvie Forlani, Ludmila Jornea, Regina Kubica Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2019


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. Mo..

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Awarded by "Investissements d'Avenir" programme

Awarded by Australian National Health and Medical Research Council (NHMRC) Program

Awarded by NHMRC

Funding Acknowledgements

We thank the families for their participation in this study, Agnes Rastetter (ICM, Paris, France) for RNA extraction, and Emmanuelle Apartis (Hopital Saint-Antoine, Paris, France) for electrophysiological assessment of Family 1. DNA extraction and cell culture of lymphoblasts have been performed at the DNA and cell bank of ICM (Paris, France). RNA-seq has been performed on the GenomEast platform of IGBMC, Illkirch, France. WGS has been performed by the Centre National de Recherche en Genomique Humaine (CNRGH) Institut de Biologie Francois Jacob, Evry, France. We thank Jean-Louis Mandel and Nicolas Charlet-Berguerand (IGBMC, Strasbourg, France), Cecile Cazeneuve (Hopital Pitie-Salpetriere, Paris, France), Charles Marcaillou (Integragen, Evry, France) and Isabel Silveira (Porto, Portugal) for valuable discussions. This study has been financially supported by three different grants from the Fondation Maladies rares to C.D. (2009, 2010, 2016), Assistance Publique des Hopitaux de Paris (APHP), INSERM, the "Investissements d'Avenir" programme ANR-10-IAIHU-06 (IHU-A-ICM), University Duisburg-Essen and University Hospital Essen. M.B. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (GNT1054618) and an NHMRC Senior Research Fellowship (GNT1102971). This work was also supported by the Victorian Government's Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme (IRIISS). Laura Canafoglia: Member of the European Reference Network on Rare and Complex epilepsies, ERN EpiCARE.