The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis
Open accessAbstract
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 neurodegeneration 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 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 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. SIGNIFICANCE: 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.
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Cites
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
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“Moreover, it has been suggested that the C9ORF72 expansion has a direct effect on the transcriptome, possibly via the formation of RNA foci [1,8]; if this is the case then transcriptome changes may represent a relatively upstream component of pathogenesis and a suitable therapeutic target.”
BackgroundA Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409
Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.036 · Cited by 1,235
Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia
Deng, H.-X., Chen, W., Hong, S.-T., Boycott, K. M., Gorrie, G. H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., et al. (2011) · Nature · doi:10.1038/nature10353 · Cited by 1,174
C9orf72 nucleotide repeat structures initiate molecular cascades of disease
Haeusler, A. R., Donnelly, C. J., Periz, G., Simko, E. A. J., Shaw, P. G., Kim, M.-S., Maragakis, N. J., Troncoso, J. C., Pandey, A., Sattler, R., et al. (2014) · Nature · doi:10.1038/nature13124 · Cited by 978
Self-citationTargeting RNA Foci in iPSC-Derived Motor Neurons from ALS Patients with a C9ORF72 Repeat Expansion
Sareen, D., O’Rourke, J. G., Meera, P., Muhammad, A. K. M. G., Grant, S., Simpkinson, M., Bell, S., Carmona, S., Ornelas, L., Sahabian, A., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3007529 · Cited by 670
Integrating Genetic and Network Analysis to Characterize Genes Related to Mouse Weight
Ghazalpour, A., Doss, S., Zhang, B., Wang, S., Plaisier, C., Castellanos, R., Brozell, A., Schadt, E. E., Drake, T. A., Lusis, A. J., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020130 · Cited by 462
Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations
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Cited by
Pun, F. W., Liu, B. H. M., Long, X., Leung, H. W., Leung, G. H. D., Mewborne, Q. T., Gao, J., Shneyderman, A., Ozerov, I. V., Wang, J., et al. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.914017 · Cited by 115
Todd, T. W., & Petrucelli, L. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13623 · Cited by 73
Disease-modifying effects of metabolic perturbations in ALS/FTLD
Jawaid, A., Khan, R., Polymenidou, M., & Schulz, P. E. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0294-0 · Cited by 37
Metadata
- Authors
- Cooper-Knock, J., Bury, J. J., Heath, P. R., Wyles, M., Higginbottom, A., Gelsthorpe, C., Highley, J. R., Hautbergue, G., Rattray, M., Kirby, J., & Shaw, P. J.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2015-05-27
- Volume
- 10
- Issue
- 5
- Pages
- e0127376
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W395020372
- Cited by
- 513
- References
- 11
- FWCI
- 11.34
- Type
- journal article
- Language
- en
- Open access
- gold
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- Cooper-Knock, J., Bury, J. J., Heath, P. R., Wyles, M., Higginbottom, A., Gelsthorpe, C., Highley, J. R., Hautbergue, G., Rattray, M., Kirby, J., & Shaw, P. J. (2015). C9ORF72 GGGGCC Expanded Repeats Produce Splicing Dysregulation which Correlates with Disease Severity in Amyotrophic Lateral Sclerosis. PLOS ONE. https://doi.org/10.1371/journal.pone.0127376
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