Major advance in genetic study of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD)
The major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was identified by researchers in 2011. A mutation known as a repeat expansion in an intron of the C9ORF72 gene was found to be the most important genetic risk factor for these disorders. Most healthy people have 25 or fewer copies of the repeat, whereas mutation carriers can have 700 copies or more. The mutation explains roughly half of familial ALS cases and about a quarter of inherited FTLD, as well as some sporadic cases. However, scientists have since puzzled over how that mutation promotes disease.
Researchers in Germany report in Science the surprising news that the intron expansions are translated into proteins. Being an expanded hexanucleotide repeat in an intron (i.e., non-coding region of DNA) the mutation should not affect the protein sequence. However, researchers found that the translated proteins contain dipeptide repeats and aggregate into deposits found in the neurons of mutation carriers, but not in people with other types of ALS/FTLD.
The discovery suggests that these dipeptide repeat proteins are major pathological players in a subset of ALS/FTLD patients. Scientists in the field hailed the findings as a major advance.