The C9orf72 hexanucleotide repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for approximately 40% of familial ALS cases and 25% of familial FTD cases. This pathogenic expansion leads to three distinct disease mechanisms: RNA foci formation, dipeptide repeat protein (DPR) toxicity, and reduced C9orf72 protein expression.
The C9orf72 gene contains a hexanucleotide repeat (GGGGCC) in its first intron. Normal individuals have 2-30 repeats, while affected individuals have hundreds to thousands of repeats. This expansion causes disease through three interconnected mechanisms:
C9orf72 Gene Structure:
Normal C9orf72 Function:
Normal vs Pathological:
Repeat RNA Properties:
The expanded repeat RNA forms nuclear RNA foci that sequester essential RNA-binding proteins:
| Protein | Function | Sequestration Effect |
|---|---|---|
| hnRNPs | RNA splicing | Splicing defects |
| Pur-α | RNA transport | Transport disruption |
| TDP-43 | RNA processing | TDP-43 mislocalization |
| ADAR | RNA editing | Editing alterations |
Five DPRs are produced through non-ATG (RAN) translation:
| DPR | Sequence | Primary Effects |
|---|---|---|
| poly-GA | Gly-Ala | Aggregate formation, proteostasis disruption |
| poly-GP | Gly-Pro | Less toxic, may have protective effects |
| poly-GR | Gly-Arg | Stress granule formation, nucleolar stress |
| poly-PA | Pro-Ala | Aggregation, synaptic dysfunction |
| poly-PR | Pro-Arg | Nuclear import disruption, nucleolar stress |
The expansion also reduces C9orf72 protein expression:
Consequences:
The study of C9Orf72 Hexanucleotide Repeat Expansion Pathway In Als And Ftd has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
DeJesus-Hernandez M, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-256. PMID:21944778
Renton AE, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257-268. PMID:21944779
Gendron TF, et al. RAN translation of repeat-associated non-ATG translated C9orf72 poly-GA, GP, GR proteins causes toxicity. Acta Neuropathol. 2013;126(4):527-543. PMID:23911023
Mori K, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339(6125):1335-1338. PMID:23344406
Gitler AD, Tsuiji H. There has been an awakening: Emerging mechanisms of C9orf72 mutations in ALS/FTD. Mol Neurodegener. 2016;11(1):53. PMID:27431916
Buchman VL, et al. C9orf72 protein: translation control. Neurobiol Aging. 2014;35(7):1528.e1-4. PMID:24503274
Liu Y, et al. C9orf72 BAC mouse model reveals neuronal degeneration and motor impairment. Front Cell Neurosci. 2016;10:171. PMID:27445696
Haeusler AR, et al. C9orf72dineptide repeats impair nucleocytoplasmic transport. Nature. 2018;556(7702):318. PMID:29670281
Page created: 2026-03-06
Tags: C9orf72, ALS, FTD, hexanucleotide repeat, RNA foci, dipeptide repeat proteins, DPR
🔴 Low Confidence
| Dimension | Score |
|---|---|
| Supporting Studies | 8 references |
| Replication | 0% |
| Effect Sizes | 25% |
| Contradicting Evidence | 0% |
| Mechanistic Completeness | 50% |
Overall Confidence: 29%