A six-nucleotide-repeat expansion in the gene C9ORF72 links the two distinct neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two groups report in Neuron.

FTD is characterized by cognitive dysfunction caused by neuron death at the surface of the brain, whereas ALS is a motor disease caused by neuron death in areas of the brain and spinal cord that control motion. These two diseases can occur together in individuals and in families, suggesting they have a common cause.

Linkage studies looking at multiple families with ALS, FTD or both previously associated a small region on chromosome 9 with these diseases in some families, but the causal gene was unknown. Now, using deep sequencing in affected families, Alan Renton et al. (doi:10.1016/j.neuron.2011.09.010) and Mariely DeJesus-Hernandez et al. (doi:10.1016/j.neuron.2011.09.011) found a GGGGCC repeat in the first intron of C9ORF72. Unaffected individuals harbored less than 20 repeats in their C9ORF72 gene, whereas subjects with either or both diseases had up to 1,600 repeats. This repeat expansion was also found in affected individuals without familial disease. From their analysis, the researchers argued that the repeat expansion seemed to be the most common genetic cause of ALS and FTD identified so far.

Although the function of C9ORF72 is unknown, its transcript can be alternatively spliced into three different variants. DeJesus-Hernandez et al. found that the expression of variant 1 is low in people with the repeat expansion and that C9ORF72 mRNA aggregates in the cell. However, further work will be needed to determine how these or other mechanisms cause neuron death in FTD and ALS.