September 30, 2011

Two independent studies published this week in the journal Neuron report on the discovery that an abnormally expanded 6-base pair DNA repeat sequence in a gene located in a region chromosome 9 (9p21) are a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). 

While the involvement of chromosome 9p21 in ALS and FTD had been known for several years, the precise genetic alteration remained elusive.  However, using next generation DNA sequencing technologies, a DNA sequence repeat element consisting of GGGGCC located in a gene of yet unknown function, C9ORF72, on chromosome 9p21 was found to be drastically expanded in ALS/FTD families previously identified to be linked to chromosome 9p21.  In healthy individuals the number of repeats was no greater than 23 but in affected individuals, the repeat size was estimated to range from 700-1600.  In a clinical series of ALS patients ascertained at the Mayo Clinic, the expansion mutation was found in 23% of familial ALS cases and 4% of sporadic cases.  Similarly, in a Finnish ALS series, 46% of familial and 21% of sporadic ALS patients harbored the expansion mutation.  Collectively, these results suggest that repeat expansion mutations in C9ORF72 is most common genetic cause of familial and sporadic ALS identified to date. 

It remains to be determined how expansion mutations in C9ORF72 cause disease.  It is possible that these mutations change expression of C9ORF72 itself, alter metabolism of other important RNA species, or confer a direct toxic property that is harmful to cells.  However, this new discovery, along with accumulating evidence from studies investigating the role of mutations in TDP-43 and FUS, further support the idea that altered RNA processing is a critical component in developing ALS.  The new discovery of expansion mutations in C9ORF72 will ultimately lead to a new genetic test and provide an exciting new target for therapy development.

 ---Steve Han MD, PhD