C9orf72 repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

Autor:	Mirceta M; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Schmidt MHM; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Shum N; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Prasolava TK; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada., Meikle B; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Lanni S; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada., Mohiuddin M; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada., McKeever PM; Tanz Centre for Research of Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, M5T 2S8, Canada., Zhang M; Tanz Centre for Research of Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, M5T 2S8, Canada.; The First Rehabilitation Hospital of Shanghai, Department of Medical Genetics, School of Medicine, Tongji University, Shanghai, 200090, China.; State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.; Advanced Study, Tongji University, Shanghai, 200092, China., Liang M; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., van der Werf I; Department of Medical Genetics, University of Antwerp, Belgium., Scheers S; Department of Medical Genetics, University of Antwerp, Belgium., Dion PA; Montreal Neurological Institute-Hospital, McGill University, 3801 University Avenue, Montreal, Quebec, H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, 3801 University Avenue, Montreal, Quebec, H3A 2B4, Canada., Wang P; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada., Wilson MD; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Abell T; Department of Biology, Tufts University, 200 Boston Avenue, Medford, MA 02155, USA., Philips EA; Department of Biology, Tufts University, 200 Boston Avenue, Medford, MA 02155, USA., Sznajder ŁJ; Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, 2033 Mowry Road, Gainesville, FL 32610-3610, USA.; Department of Chemistry and Biochemistry, University of Nevada, 4003-4505 South Maryland Parkway, Las Vegas, NV 89154, USA., Swanson MS; Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, College of Medicine, University of Florida, 2033 Mowry Road, Gainesville, FL 32610-3610, USA., Mehkary M; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Khan M; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Yokoi K; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada., Jung C; BACPAC Resource Center, Children's Hospital Oakland Research Institute, 25129 NE 42nd Pl, Redmond, WA 98053, USA., de Jong PJ; BACPAC Resource Center, Children's Hospital Oakland Research Institute, 25129 NE 42nd Pl, Redmond, WA 98053, USA., Freudenreich CH; Department of Biology, Tufts University, 200 Boston Avenue, Medford, MA 02155, USA., McGoldrick P; Tanz Centre for Research of Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, M5T 2S8, Canada., Yuen RKC; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada., Abrahão A; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, North York, Toronto, ON, M4N 3M5, Canada., Keith J; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, North York, Toronto, ON, M4N 3M5, Canada., Zinman L; Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, North York, Toronto, ON, M4N 3M5, Canada., Robertson J; Tanz Centre for Research of Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, M5T 2S8, Canada., Rogaeva E; Tanz Centre for Research of Neurodegenerative Diseases, University of Toronto, 60 Leonard Avenue, Toronto, M5T 2S8, Canada., Rouleau GA; Montreal Neurological Institute-Hospital, McGill University, 3801 University Avenue, Montreal, Quebec, H3A 2B4, Canada.; Department of Neurology and Neurosurgery, McGill University, 3801 University Avenue, Montreal, Quebec, H3A 2B4, Canada.; Department of Human Genetics, McGill University, 3801 University Avenue, Montreal, Quebec, H3A 2B4, Canada., Kooy RF; Department of Medical Genetics, University of Antwerp, Belgium., Pearson CE; Program of Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON, M3S 1A8, Canada.
Jazyk:	angličtina
Zdroj:	NAR molecular medicine [NAR Mol Med] 2024 Nov 12; Vol. 1 (4), pp. ugae019. Date of Electronic Publication: 2024 Nov 12 (Print Publication: 2024).
DOI:	10.1093/narmme/ugae019
Abstrakt:	The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and C9orf72 , is linked to multiple diseases. C9orf72 (GGGGCC)n expansions ( C9orf72 Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. C9orf72 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 C9orf72 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 C9orf72 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. C9orf72 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 C9orf72 Exp patient contained a highly rearranged FRA9A-expressing Chr9 with Chr9-wide dysregulated gene expression. Somatic C9orf72 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 C9orf72 Exp mice, implicating C9orf72 Exp as the source. Our results highlight unappreciated effects of C9orf72 expansions that trigger vitamin-sensitive chromosome fragility, adding structural variations to the disease-enriched 9p21 locus, and likely elsewhere. (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Molecular Medicine.)
Databáze:	MEDLINE
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