RESEARCH ARTICLE C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis

Objective An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neuro-degeneration is unknown, but a direct effect on RNA processing mediated by RNA foci tran-scribed from the repeat sequence has been proposed. Methods Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblas-toid cell lines derived from human ALS patients, including those with an expansion of C9ORF72, and controls. In lymphoblastoid cell lines, expansion length and the frequency of sense and antisense RNA foci was also examined. Results Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding ‘RNA splicing ’ proteins. There was a significant overlap of these genes with an independentl