The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter
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Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
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Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia, along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms.
“Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia [206,210,211], along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms [205,206].”
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RNA Misprocessing in C9orf72-Linked Neurodegeneration
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Epigenetic Modulation of Microglia Function and Phenotypes in Neurodegenerative Diseases
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- Authors
- on behalf of the BELNEU CONSORTIUM, Gijselinck, I., Van Mossevelde, S., van der Zee, J., Sieben, A., Engelborghs, S., De Bleecker, J., Ivanoiu, A., Deryck, O., Edbauer, D., Zhang, M., Heeman, B., Bäumer, V, Van den Broeck, M., Mattheijssens, M., Peeters, K., Rogaeva, E., De Jonghe, P., Cras, P., Martin, J.-J., de Deyn, P. P., Cruts, M., & Van Broeckhoven, C.
- Affiliations
- University of Antwerp (BE)
- UCLouvain (BE)
- AZ Sint-Jan (BE)
- German Center for Neurodegenerative Diseases (DE)
- University of Toronto (CA)
- Corresponding author
- Cruts, M
- Venue
- Molecular Psychiatry
- Published
- 2015-10-20
- Volume
- 21
- Issue
- 8
- Pages
- 1112-1124
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4960451
- OpenAlex
- W1837901569
- Cited by
- 242
- References
- 83
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 19 · 2022: 27 · 2021: 32 · 2020: 29 · 2019: 30 · 2018: 28 · 2017: 23 · 2016: 13 · 2015: 5
- FWCI
- 16.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
- Digital Access to Libraries (submittedVersion, other-oa)
- DZNE Pub (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- MetLife Foundation
- Belgian Federal Science Policy Office
- Fonds Wetenschappelijk Onderzoek
- Universiteit Antwerpen
- Vlaamse regering
- Instituut Born-Bunge
- Fondation pour la Recherche sur Alzheimer
- FP7 Ideas: European Research Council (617198)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72, G4C2 repeat expansion, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, age of onset, genetic anticipation, DNA methylation, CpG islands, promoter activity, transcriptional downregulation, mosaicism, loss of function, gain-of-function, familial ALS, genetic counseling
- MeSH terms
- C9orf72 Protein, Adult, Amyotrophic Lateral Sclerosis, Belgium, Female, Humans, Male, Middle Aged, Promoter Regions, Genetic, Proteins, Down-Regulation, Age of Onset, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, Frontotemporal Lobar Degeneration, Epigenomics
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