Autor(es):
Tazelaar, Gijs H.P. ; Hop, Paul J. ; Seelen, Meinie ; van Vugt, Joke J.F.A. ; van Rheenen, Wouter ; Kool, Lindy ; van Eijk, Kristel R. ; Gijzen, Marleen ; Dooijes, Dennis ; Moisse, Matthieu ; Calvo, Andrea ; Moglia, Cristina ; Brunetti, Maura ; Canosa, Antonio ; Nordin, Angelica ; Pardina, Jesus S. Mora ; Ravits, John ; Al-Chalabi, Ammar ; Chio, Adriano ; McLaughlin, Russell L. ; Hardiman, Orla ; Van Damme, Philip ; Carvalho, Mamede ; Neuwirth, Christoph ; Weber, Markus ; Andersen, Peter M ; van den Berg, Leonard H. ; Veldink, Jan H. ; van Es, Michael A.
Data: 2023
Identificador Persistente: http://hdl.handle.net/10451/55900
Origem: Repositório da Universidade de Lisboa
Assunto(s): Amyotrophic Lateral Sclerosis; Genetic modifiers; Post-zygotic mutations; Repeat expansions
Descrição
Amyotrophic lateral sclerosis is a heterogeneous, fatal neurodegenerative disease, characterized by motor neuron loss and in 50% of cases also by cognitive and/or behavioral changes. Mendelian forms of ALS comprise approximately 10-15% of cases. The majority is however considered sporadic, but also with a high contribution of genetic risk factors. To explore the contribution of somatic mutations and/or epigenetic changes to disease risk, we performed whole genome sequencing and methylation analyses using samples from multiple tissues on a cohort of 26 monozygotic twins discordant for ALS, followed by in-depth validation and replication experiments. The results of these analyses implicate several mechanisms in ALS pathophysiology, which include a role for de novo mutations, defects in DNA damage repair and accelerated aging.
