C9ORF72 – how do problems in this gene cause FTD and motor neurone disease?

Recent studies have shown that mutations in a gene called C9orf72 are a major cause of not only FTD but also motor neurone disease. Researchers are now trying to work out exactly what the mechanisms are that lead to disease.

In 2011 two research groups independently discovered a mutation in a gene called C9ORF72 as a common genetic cause of FTD and motor neurone disease (MND). More specifically, 6 DNA nucleotides (GGGGCC) were found to be repeated hundreds of times near the start of the C9ORF72 gene in MND and FTD patients, whereas the number of repeats in healthy individuals is only up to around 25. Little is known about the normal function of C9ORF72 and since the discovery of its role in FTD and MND there has been a great deal of research focused on understanding what this gene normally does and what goes wrong in disease.

New light into the mechanism of disease

Normally, the message carried by our genes is passed into an intermediate product called RNA, which is then processed to give rise to proteins. During this processing from RNA to protein, certain bits of the RNA are removed and are not going to be part of the protein. The expanded repeat in C9ORF72 gene is located in one of these regions which are removed from RNA and therefore are absent from the protein. This fact along with some preliminary experiments has led researchers to form two main hypotheses about the possible mechanism by which this repeat might cause disease:

  • One is that the repeat generates RNA products which due to the extended repeat cannot be processed as they should, and therefore end up aggregating inside the cells, creating a source of toxicity.
  • The other is that the repeat completely disrupts the formation of RNA products.

Although these two mechanisms point towards different paths that might go wrong due to the mutation, they both agree that the repeat itself cannot be part of the C9ORF72 protein.

However, recently, a new third possible mechanism came to the foreground by Dieter Edbauer of Ludwig-Maximilians University and Leonard Petrucelli of the Mayo Clinic who independently showed that the GGGGCC repeats in C9ORF72 give rise to proteins consisting of two-aminoacid-repeats. Both groups detected aggregates of these repeat proteins in brain tissue of patients carrying the mutation whereas the aggregates were absent from individuals without the mutation.

Significance of findings

The importance of these findings is great. Not only do they shed light on a new mechanism previously not considered, but they also provide new insight into the potential use of these two-aminoacid-repeat proteins as disease biomarkers as well as therapeutic targets. Researchers now need to address whether these repeat proteins are toxic with a central role in disease development or just harmless by-products of the expanded repeat.


Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, Haass C, Edbauer D. The C9ORF72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339(6125):1335-8.

Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, Boylan KB, Dickson DW, Petrucelli L. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77(4):639–46.

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