Chromosome 9 open reading frame 72 hexanucleotide repeat-containing RNA (sense) (C9orf72 G4C2 RNA) (C9orf72 G4C2 RNA)

C9orf72 G4C2 sense repeat-containing RNA transcripts are pathological RNA molecules generated from a hexanucleotide repeat expansion (GGGGCC) within the C9orf72 gene [DeJesus-Hernandez et al., 2011]. This genetic mutation is the leading cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [Renton et al., 2011]. The sense transcripts contribute to neurodegeneration by forming nuclear RNA foci that sequester vital RNA-binding proteins, disrupting cellular RNA processing [Mizielinska et al., 2014]. Additionally, these transcripts undergo repeat-associated non-AUG (RAN) translation, producing toxic dipeptide repeat proteins (DPRs) such as poly-GP, poly-GA, and poly-GR [Ash et al., 2013]. Therapeutic development primarily targets these sense transcripts using antisense oligonucleotides (ASOs) to promote their degradation or small molecules to interfere with their toxic interactions [Lagier-Tourenne et al., 2013]. Monitoring of dipeptide repeat proteins in cerebrospinal fluid serves as a key biomarker for target engagement in clinical trials [Gendron et al., 2017]. Despite the failure of early clinical candidates like BIIB078, the reduction of these toxic transcripts remains a central strategy in treating C9orf72-associated neurodegeneration [Tran et al., 2022].

Other names

C9orf72 hexanucleotide repeat expansion RNAGGGGCC repeat RNASense C9orf72 HRE RNAC9orf72 G4C2 transcripts

Antisense oligonucleotides (ASOs) target the sense transcripts for RNase H-mediated degradation to reduce toxic RNA and dipeptide repeat protein levels [Lagier-Tourenne et al., 2013].