ReviewC9orf72; abnormal RNA expression is the key

- C9Orf72 mutations are the most common cause of familial FTD and ALS.
- The C9Orf72 mutation is an expanded hexanucleotide repeat.
- Abberant RNA species are expressed from the repeat.
- The abberrant RNA is translated in dipeptide proteins.
- C9Orf72 is predicted to be a DENN domain protein.

An expanded GGGGCC hexanucleotide repeat in the first intron located between the 1st and 2nd non-coding exons of C9orf72 is the most frequent cause of frontotemporal dementia (FTD) and amyothropic lateral sclerosis (ALS).C9orf72 is a protein with largely unknown function and insight into the disease mechanism caused by the repeat expansion is still in an early stage but increases at an amazing pace. Three main hypotheses are currently being considered to explain the disease process including haploinsuffiency due to the loss of expression from the mutated allele, RNA toxicity caused by accumulation of repeat containing transcripts and toxic protein species generated by the abnormal translation of repeat sequences. We review the current status of genetic, population and functional data and discuss the current insights into the biology of C9orf72 and this repeat expansion disease.