C9orf72

C9orf72 is a gene located on the short arm (p) of chromosome 9 at position 21.2 in humans. Its name derives from its location: Chromosome 9, open reading frame 72. The protein encoded by the C9orf72 gene is thought to play a role in membrane trafficking and autophagy, though its precise function remains under investigation.

The C9orf72 gene is most well-known for a hexanucleotide repeat expansion (GGGGCC) in its non-coding region. This repeat expansion is a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), collectively known as C9orf72-ALS/FTD. Healthy individuals typically have fewer than 30 repeats, while individuals with the expanded repeat may have hundreds or even thousands of repeats.

The mechanisms by which the repeat expansion leads to neurodegeneration are complex and not fully understood, but are believed to involve multiple pathways including:

• RNA toxicity: The expanded GGGGCC repeat RNA can form stable secondary structures that sequester RNA-binding proteins, disrupting normal cellular processes.
• Repeat-associated non-ATG (RAN) translation: The expanded repeat can be translated into toxic dipeptide repeat proteins (DPRs) in the absence of a start codon. These DPRs aggregate and interfere with cellular function.
• Loss of function: The repeat expansion may reduce the normal expression of the C9orf72 protein, contributing to disease pathology.

Genetic testing for the C9orf72 repeat expansion is available and can be used to diagnose C9orf72-ALS/FTD. There is currently no cure for C9orf72-ALS/FTD, and treatment focuses on managing symptoms and improving quality of life. Research is ongoing to develop therapies that target the underlying mechanisms of the disease.