Chromosome 9 open reading frame 72 G4C2 sense repeat RNA transcripts (C9orf72 HRE sense RNA)

The Chromosome 9 open reading frame 72 (C9orf72) G4C2 sense repeat RNA transcripts are pathological RNA species generated from the hexanucleotide repeat expansion (HRE) in the first intron of the C9orf72 gene [1, 8]. This expansion, typically consisting of hundreds to thousands of GGGGCC repeats, is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [3, 10]. These sense transcripts fold into complex secondary structures, such as G-quadruplexes and hairpins, which aggregate into nuclear RNA foci and sequester essential RNA-binding proteins, thereby disrupting RNA processing and nucleocytoplasmic transport [1, 12]. Furthermore, the transcripts serve as templates for repeat-associated non-AUG (RAN) translation, producing toxic dipeptide repeat proteins (DPRs) like poly-GA, poly-GR, and poly-GP that aggregate in the brains of affected individuals [3, 15]. Therapeutic efforts have largely focused on using antisense oligonucleotides (ASOs) and RNA interference to selectively degrade these toxic transcripts or block their translation [3, 14]. However, recent clinical trial failures of major ASO candidates like BIIB078 and WVE-004 have highlighted the complexity of the disease, suggesting that both gain-of-toxicity from RNA/DPRs and loss-of-function from reduced C9orf72 protein levels may contribute to pathogenesis [21, 24].

Other names

C9orf72 hexanucleotide repeat expansion sense RNAGGGGCC repeat RNAr(G4C2)nC9orf72 HRE sense transcriptsG4C2 sense RNA

RNase H-mediated degradation of repeat-containing RNA and steric blocking of RNA-binding protein sequestration and RAN translation [3, 14].