<i>C9orf72</i> repeat expansion creates the unstable folate-sensitive fragile site FRA9A
The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and <i>C9orf72</i>, is linked to multiple diseases. <i>C9orf72</i> (GGGGCC)n expansions (<i>C9orf72</i>Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. <i>C9orf72</i>Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown. Here, we show <i>C9orf72</i>Exp in pre-symptomatic and amyotrophic lateral sclerosis-frontotemporal dementia patient cells and brains cause the folate-sensitive chromosomal fragile site, FRA9A. FRA9A centers on >33 kb of <i>C9orf72</i> as highly compacted chromatin embedded in an 8.2 Mb fragility zone spanning 9p21, encompassing 46 genes, making FRA9A one of the largest fragile sites. <i>C9orf72</i>Exp cells show chromosomal instability, heightened global- and Chr9p-enriched sister-chromatid exchanges, truncated-Chr9s, acentric-Chr9s and Chr9-containing micronuclei, providing endogenous sources of damaged and immunostimulatory DNA. Cells from one <i>C9orf72</i>Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic <i>C9orf72</i>Exp repeat instability and chromosomal fragility are sensitive to folate deficiency. Age-dependent repeat instability, chromosomal fragility and chromosomal instability can be transferred to CNS and peripheral tissues of transgenic <i>C9orf72</i>Exp mice, implicating <i>C9orf72</i>Exp as the source. Our results highlight unappreciated effects of <i>C9orf72</i> expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere.
Authors
- Guy A. Rouleau (ORCID: https://orcid.org/0000-0001-8403-1418)
- Elliot A. Philips (ORCID: https://orcid.org/0000-0002-6407-1890)
- Janice Robertson (ORCID: https://orcid.org/0000-0002-5499-9943)
- Monika H.M. Schmidt (ORCID: https://orcid.org/0000-0002-0131-332X)
- Stella Lanni (ORCID: https://orcid.org/0000-0003-3233-9204)
- Natalie Shum
- Ekaterina Rogaeva (ORCID: https://orcid.org/0000-0002-2852-0329)
- Mohiuddin Mohiuddin (ORCID: https://orcid.org/0000-0003-1899-6734)
- Mahreen Khan (ORCID: https://orcid.org/0000-0002-9900-978X)
- Michael D. Wilson (ORCID: https://orcid.org/0000-0002-4015-3066)
- Ryan K. C. Yuen (ORCID: https://orcid.org/0000-0001-7273-4968)
- Mustafa Mehkary (ORCID: https://orcid.org/0009-0003-5791-8285)
- Catherine H. Freudenreich (ORCID: https://orcid.org/0000-0002-1652-2917)
- T B ABELL
- Ilse van der Werf (ORCID: https://orcid.org/0000-0002-3089-395X)
- Agessandro Abrahão (ORCID: https://orcid.org/0000-0003-1142-2842)
- Katsuyuki Yokoi (ORCID: https://orcid.org/0000-0002-4760-0420)
- Maurice S. Swanson (ORCID: https://orcid.org/0000-0001-6245-5367)
- Christopher E. Pearson (ORCID: https://orcid.org/0000-0001-9545-4205)
- Patrick A. Dion (ORCID: https://orcid.org/0000-0002-2099-954X)
- Paul M. McKeever (ORCID: https://orcid.org/0000-0002-9464-141X)
- Ming Zhang (ORCID: https://orcid.org/0000-0003-2728-128X)
- Julia Keith (ORCID: https://orcid.org/0000-0003-1519-6731)
- R. Frank Kooy (ORCID: https://orcid.org/0000-0003-2024-0485)
- Tanya Prasolava
- Łukasz J. Sznajder (ORCID: https://orcid.org/0000-0001-6822-6485)
- Minggao Liang
- Mila Mirceta
- Pieter J. de Jong (ORCID: https://orcid.org/0000-0002-7972-5260)
- Peixiang Wang (ORCID: https://orcid.org/0000-0002-6440-8238)
- Lorne Zinman
- Philip McGoldrick
- Christine Jung
- Stefaan Scheers
- Bryanna Meikle
Institutions
- Tongji University (CN)
- Tufts University (US)
- Montreal Neurological Institute and Hospital (CA)
- Sunnybrook Health Science Centre (CA)
- University of Nevada, Las Vegas (US)
- University of Antwerp (BE)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Canada Research Chairs (CA)
- Health Sciences Centre (CA)
- University of Florida (US)
- Occupational Cancer Research Centre (CA)
- Shanghai East Hospital (CN)
- SickKids Foundation (CA)
- McGill University (CA)
Publication Details
- Journal
- NAR Molecular Medicine
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1093/narmme/ugae019
- Citations
- 12
- Primary Topic
- Genetics and Neurodevelopmental Disorders
- Type
- article
- Field-Weighted Citation Impact
- 6.60
Funders
- Consortium canadien en neurodégénérescence associée au vieillissement
- Weston Family Foundation
- W. Garfield Weston Foundation
- National Natural Science Foundation of China
- National Institutes of Health
- H2020 Public-public partnerships