Dataset Information

Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease.

ABSTRACT: BACKGROUND:We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders. METHODS:We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified haplotype carriers, the C9ORF72 repeat was genotyped using the repeat-primed polymerase chain reaction assay. RESULTS:No larger (intermediate or expanded) repeats were found in these autopsy-confirmed PD samples. This absence of larger repeats is significantly different from the frequency in clinically diagnosed datasets (P?=?0.002). CONCLUSIONS:Our results suggest that expanded or intermediate C9ORF72 repeats in clinically diagnosed PD or parkinsonism might be an indication of heterogeneity in clinically diagnosed PD cases. Further studies are needed to elucidate the potential contribution of the C9ORF72 repeat to autopsy-confirmed PD.

SUBMITTER: Nuytemans K

PROVIDER: S-EPMC4022044 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease.

Nuytemans Karen K Inchausti Vanessa V Beecham Gary W GW Wang Liyong L Dickson Dennis W DW Trojanowski John Q JQ Lee Virginia M-Y VM Mash Deborah C DC Frosch Matthew P MP Foroud Tatiana M TM Honig Lawrence S LS Montine Thomas J TJ Dawson Ted M TM Martin Eden R ER Scott William K WK Vance Jeffery M JM

Movement disorders : official journal of the Movement Disorder Society 20140226 6

<h4>Background</h4>We have reported that intermediate repeat lengths of the C9ORF72 repeat are a risk factor for Parkinson's disease (PD) in a clinically diagnosed data set. Because 10% to 25% of clinically diagnosed PD have different diagnoses upon autopsy, we hypothesized that this may reflect phenotypic heterogeneity or concomitant pathology of other neurodegenerative disorders.<h4>Methods</h4>We screened 488 autopsy-confirmed PD cases for expansion haplotype tag rs3849942T. In 196 identified ...[more]

PMID: 24573903

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Project description:An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed.Gene expression profiling utilised total RNA extracted from motor neurons and lymphoblastoid 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.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 C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length.Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 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.

Dataset Information

Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease.

Publications

Absence of C9ORF72 expanded or intermediate repeats in autopsy-confirmed Parkinson's disease.

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