OBJECTIVE: An intronic GGGGCC-repeat expansion of @entity3301 is the most common genetic variant of @entity746 ( @entity746 ) and @entity4943 . The mechanism of @entity179 is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed. METHODS: Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblastoid cell lines derived from @entity1 @entity746 @entity1 , including those with an expansion of @entity3301 , 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 independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from @entity3301 - @entity746 @entity1 splicing consistency was lower than in lines derived from non- @entity3301 @entity746 @entity1 or controls; furthermore splicing consistency was lower in samples derived from @entity1 with @entity74 . Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from @entity1 with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length. SIGNIFICANCE: Up-regulation of genes encoding predicted binding partners of the @entity3301 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by @entity3301 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity.

@entity3301 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in XXXX .

@entity1 :: ('9606', 'Species') :: ['human', 'patients'] @entity179 :: ('MESH:D019636', 'Disease') :: ['neurodegeneration'] @entity74 :: ('MESH:D030342', 'Disease') :: ['faster disease progression'] @entity3301 :: ('203228', 'Gene') :: ['C9ORF72'] @entity746 :: ('MESH:D000690', 'Disease') :: ['ALS', 'amyotrophic lateral sclerosis'] @entity4943 :: ('MESH:D057180', 'Disease') :: ['frontotemporal dementia']
@entity746 :: (MESH:D000690,Disease) :: ['Amyotrophic Lateral Sclerosis']
