title: Disease Mechanisms ofC9ORF72Repeat Expansions.
abstract: G4C2repeat expansions within theC9ORF72gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These bidirectionally transcribed expansions lead to (1) the accumulation of sense G4C2and antisense G2C4repeat-containing RNA, (2) the production of proteins of repeating dipeptides through unconventional translation of these transcripts, and (3) decreasedC9ORF72mRNA and protein expression. Consequently, there is ample opportunity for theC9ORF72mutation to give rise to a spectrum of clinical manifestations, ranging from muscle weakness and atrophy to changes in behavior and cognition. It is thus somewhat surprising that investigations of these three seemingly disparate events often converge on similar putative pathological mechanisms. This review aims to summarize the findings and questions emerging from the field's quest to decipher howC9ORF72repeat expansions cause the devastating diseases collectively referred to as "c9ALS/FTD."
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224.
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000073885:C9orf72 Protein / Q000235:genetics*; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D059368:RNA Isoforms / Q000378:metabolism; D016372:RNA, Antisense / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D059368:RNA Isoforms; D016372:RNA, Antisense