The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-08

AUTHORS

I Gijselinck, S Van Mossevelde, J van der Zee, A Sieben, S Engelborghs, J De Bleecker, A Ivanoiu, O Deryck, D Edbauer, M Zhang, B Heeman, V Bäumer, M Van den Broeck, M Mattheijssens, K Peeters, E Rogaeva, P De Jonghe, P Cras, J-J Martin, P P de Deyn, M Cruts, C Van Broeckhoven

ABSTRACT

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. More... »

PAGES

1112-1124

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/mp.2015.159

    DOI

    http://dx.doi.org/10.1038/mp.2015.159

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1004877438

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26481318


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    556 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
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    558 https://www.grid.ac/institutes/grid.5284.b schema:alternateName University of Antwerp
    559 schema:name Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium.
    560 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
    561 Neurodegenerative Brain Diseases Group VIB Department of Molecular Genetics, Antwerp, Belgium.
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    563 https://www.grid.ac/institutes/grid.5342.0 schema:alternateName Ghent University
    564 schema:name Department of Neurology, University Hospital Ghent and University of Ghent, Ghent, Belgium.
    565 Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
    566 Neurodegenerative Brain Diseases Group VIB Department of Molecular Genetics, Antwerp, Belgium.
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    568 https://www.grid.ac/institutes/grid.7942.8 schema:alternateName Université Catholique de Louvain
    569 schema:name Department of Neurology, Saint-Luc University Hospital and Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium.
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