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; Mathieu Alexandre; 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; FAME consortium

doi:10.1038/s41467-019-12763-9

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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

Rahel Florian, Florian Kraft, Elsa Leitão, Sabine Kaya, Stephan Klebe, Eloi Magnin, Anne-Fleur van Rootselaar, Julien Buratti, Theresa Kühnel, Christopher Schröder, …

Nature communications, Vol.10(1), pp.4919-14

29/10/2019

DOI: https://doi.org/10.1038/s41467-019-12763-9

PMID: 31664039

Résumé

Adolescent

Adult

Aged

Chromosome Mapping

DNA Repeat Expansion

Epilepsies, Myoclonic/genetics

Female

Genetics

Human genetics

Humans

Introns

Life Sciences

Male

Membrane Proteins/genetics

Middle Aged

Pedigree

Ubiquitin-Protein Ligases/genetics

Young Adult

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.

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Titre: Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Créateurs - sans rôle: Rahel Florian - Institute of Human Genetics - Institut für Humangenetik [Essen]
Florian Kraft - RWTH Aachen University = Rheinisch-Westfälische Technische Hochschule Aachen
Elsa Leitão - Institute of Human Genetics - Institut für Humangenetik [Essen]
Sabine Kaya - Institute of Human Genetics - Institut für Humangenetik [Essen]
Stephan Klebe - Universitätsklinikum Essen [Universität Duisburg-Essen]
Eloi Magnin - Centre Hospitalier Régional Universitaire de Besançon
Anne-Fleur van Rootselaar - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
Julien Buratti - CHU Pitié-Salpêtrière [AP-HP]
Theresa Kühnel - Institute of Human Genetics - Institut für Humangenetik [Essen]
Christopher Schröder - Institute of Human Genetics - Institut für Humangenetik [Essen]
Sebastian Giesselmann - RWTH Aachen University = Rheinisch-Westfälische Technische Hochschule Aachen
Nikolai Tschernoster - Centre for Molecular Medicine Cologne [Cologne]
Janine Altmueller - Cologne Center for Genomics [Cologne]
Anaide Lamiral - Centre Hospitalier Régional Universitaire de Besançon
Boris Keren - CHU Pitié-Salpêtrière [AP-HP]
Caroline Nava - CHU Pitié-Salpêtrière [AP-HP]
Delphine Bouteiller - Institut du Cerveau
Sylvie Forlani - Institut du Cerveau
Ludmila Jornea - Institut du Cerveau
Regina Kubica - Institute of Human Genetics - Institut für Humangenetik [Essen]
Tao Ye - Institut de Génétique et de Biologie Moléculaire et Cellulaire
Damien Plassard - Institut de Génétique et de Biologie Moléculaire et Cellulaire
Bernard Jost - Institut de Génétique et de Biologie Moléculaire et Cellulaire
Vincent Meyer - Institut de biologie François Jacob
Jean-François Deleuze - Institut de Biologie François JACOB
Yannick Delpu - genomic vision
Mario Avarello - genomic vision
Lisanne Vijfhuizen - Leiden University Medical Center
Gabrielle Rudolf - Institut de Génétique et de Biologie Moléculaire et Cellulaire
Edouard Hirsch - Service de Neurologie [Strasbourg]
Thessa Kroes - School of Biological Sciences [Adelaïde]
Philipp Reif - Goethe University Frankfurt = Goethe-Universität Frankfurt am Main
Felix Rosenow - Goethe University Frankfurt = Goethe-Universität Frankfurt am Main
Christos Ganos - Charité - UniversitätsMedizin = Berlin University Medicine
Marie Vidailhet - Institut du Cerveau = Paris Brain Institute
Lionel Thivard - CHU Pitié-Salpêtrière [AP-HP]
Mathieu Alexandre - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
Thomas Bourgeron - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
Ingo Kurth - RWTH Aachen University = Rheinisch-Westfälische Technische Hochschule Aachen
Haloom Rafehi - The Walter and Eliza Hall Institute of Medical Research
Laura Steenpass - Institute of Human Genetics - Institut für Humangenetik [Essen]
Bernhard Horsthemke - Institute of Human Genetics - Institut für Humangenetik [Essen]
Eric Leguern - CHU Pitié-Salpêtrière [AP-HP]
Karl Martin Klein - Goethe University Frankfurt = Goethe-Universität Frankfurt am Main
Pierre Labauge - Hôpital Gui de Chauliac [CHU Montpellier]
Mark Bennett - The Walter and Eliza Hall Institute of Medical Research
Melanie Bahlo - Walter and Eliza Hall Institute of Medical Research
Jozef Gecz - The University of Adelaide
Mark Corbett - University of Adelaide
Marina Tijssen - University Medical Center Groningen [Groningen]
Arn van den Maagdenberg - Leiden University Medical Center [Leiden]
Christel Depienne - Institute of Human Genetics - Institut für Humangenetik [Essen]
FAME consortium
Détails de publication: Nature communications, Vol.10(1), pp.4919-14
Éditeur: Nature Publishing Group
Identifiants: 99148872209311
Unité académique: Recherche hors université
Langue: English
Type de ressource: Journal article