Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 10 2019
29 10 2019
Historique:
received:
19
03
2019
accepted:
23
09
2019
entrez:
31
10
2019
pubmed:
31
10
2019
medline:
26
2
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31664039
doi: 10.1038/s41467-019-12763-9
pii: 10.1038/s41467-019-12763-9
pmc: PMC6820781
doi:
Substances chimiques
Membrane Proteins
0
MARCHF6 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4919Investigateurs
Samuel F Berkovic
(SF)
Francesca Bisulli
(F)
Francesco Brancati
(F)
Laura Canafoglia
(L)
Giorgio Casari
(G)
Renzo Guerrini
(R)
Hiroyuki Ishiura
(H)
Laura Licchetta
(L)
Davide Mei
(D)
Tommaso Pippucci
(T)
Lynette Sadleir
(L)
Ingrid E Scheffer
(IE)
Pasquale Striano
(P)
Paolo Tinuper
(P)
Shoji Tsuji
(S)
Federico Zara
(F)
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