Chromosome 9 open reading frame 72 (C9orf72) (C9orf72)

Chromosome 9 open reading frame 72 (C9orf72) is a gene whose hexanucleotide (GGGGCC) repeat expansion in the first intron is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The C9orf72 protein functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases, playing a critical role in endosomal trafficking, autophagy, and lysosomal function (Sellier et al., 2016; UniProt Q96LT7). In disease states, the expansion leads to three primary pathogenic mechanisms: loss of C9orf72 protein function (haploinsufficiency), toxic gain-of-function from RNA foci, and the production of toxic dipeptide repeat (DPR) proteins through non-canonical translation (Taylor et al., 2016). Therapeutic strategies primarily focus on using antisense oligonucleotides (ASOs) or gene therapy to selectively reduce the levels of expansion-containing transcripts while preserving the expression of the wild-type allele (Lagier-Tourenne et al., 2013). Despite several high-profile clinical trial failures, such as BIIB078 and WVE-004, C9orf72 remains a high-priority target for neurodegenerative disease modification (Biogen, 2022; Wave Life Sciences, 2023).

Other names

ALSFTDFTDALS1DENNL72C9orf72-SMCR8 complex

Antisense-mediated degradation of hexanucleotide repeat-containing RNA transcripts to reduce toxic gain-of-function from RNA foci and dipeptide repeat protein production (Lagier-Tourenne et al., 2013; Smith et al., 2017).