Chromosome 9 open reading frame 72 hexanucleotide repeat expansion-containing transcript (C9orf72 V1/V3 mutant transcripts)

C9orf72 V1/V3 mutant transcripts are specific RNA isoforms of the Chromosome 9 open reading frame 72 gene that contain a pathogenic GGGGCC hexanucleotide repeat expansion (DeJesus-Hernandez et al., 2011). This expansion, typically located in the first intron of these variants, is the leading genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Renton et al., 2011). The presence of these mutant transcripts leads to neurotoxicity through the formation of RNA foci that sequester critical RNA-binding proteins, disrupting cellular RNA metabolism. Additionally, these transcripts undergo repeat-associated non-AUG (RAN) translation, producing toxic dipeptide repeat proteins (DPRs) such as poly-GP and poly-GR that accumulate in the central nervous system (Gendron et al., 2017). Therapeutic interventions, such as antisense oligonucleotides (ASOs), are designed to bind and trigger the degradation of these specific transcripts to reduce the burden of toxic RNA and DPRs. While targeting these transcripts shows promise in preclinical models, clinical trials like those for BIIB078 and WVE-004 have faced challenges regarding efficacy and the potential for C9orf72 protein haploinsufficiency (Tran et al., 2022). Monitoring of dipeptide repeat proteins in the cerebrospinal fluid serves as a key biomarker for assessing the engagement and effectiveness of these therapies (Gendron et al., 2017).

Other names

C9orf72 G4C2 repeat-containing RNAC9orf72 sense transcriptsC9orf72 HRE transcriptsC9orf72 variant 1 and 3 mutant RNA

Antisense oligonucleotide-mediated RNase H degradation of expansion-containing RNA transcripts