ArticleActa neuropathologica2015
Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier.
Article in Acta neuropathologica, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 2 of them syntheses that pooled it.
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Who cites it
77 citing papers in PubMed, 2 syntheses or guidelines pooled it, 126 citations in OpenAlex.
- Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.Science translational medicine · 2022Pooled it
- Blood DNA methylation as a potential biomarker of dementia: A systematic review.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2018Pooled it
- PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- "Assessing relationship between blood MAPT methylation levels and clinical expression in Frontotemporal Dementia".Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Observational
- Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes.Molecular neurodegeneration · 2025Article
- Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Analysis of C9orf72 repeat length in progressive supranuclear palsy, corticobasal syndrome, corticobasal degeneration, and atypical parkinsonism.Journal of neurology · 2025Article
- The Promise of Epigenetic Editing for Treating Brain Disorders.Sub-cellular biochemistry · 2025Review
- Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.Molecular neurodegeneration · 2024Article
- Article
- Review
- Abundant transcriptomic alterations in the human cerebellum of patients with a C9orf72 repeat expansion.Acta neuropathologica · 2024Article
- Distinctive cell-free DNA methylation characterizes presymptomatic genetic frontotemporal dementia.Annals of clinical and translational neurology · 2024Article
- R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases.Molecular neurobiology · 2023Review
- Utility of DNA Methylation as a Biomarker in Aging and Alzheimer's Disease.Journal of Alzheimer's disease reports · 2023Review
- Clinical and genetic features of amyotrophic lateral sclerosis patients withBrain communications · 2023Article
- The DNA Methylation in Neurological Diseases.Cells · 2022Review
- Genetic and Epigenetic Interplay Define Disease Onset and Severity in Repeat Diseases.Frontiers in aging neuroscience · 2022Review
- The effects of molecular crowding and CpG hypermethylation on DNA G-quadruplexes formed by the C9orf72 nucleotide repeat expansion.Scientific reports · 2021Article
- Molecular mechanisms underlying nucleotide repeat expansion disorders.Nature reviews. Molecular cell biology · 2021Review
17 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members. Multivariate regression models were used to determine whether C9orf72 hypermethylation was associated with age at onset, disease duration, age at death, or hexanucleotide repeat expansion size. Permutation analysis was performed to determine whether C9orf72 methylation is heritable. We observed a high correlation between C9orf72 methylation across tissues including cerebellum, frontal cortex, spinal cord and peripheral blood. While C9orf72 methylation was not significantly different between ALS and FTD and did not predict age at onset, brain and blood C9orf72 hypermethylation was associated with later age at death in FTD (brain: β = 0.18, p = 0.006; blood: β = 0.15, p < 0.001), and blood C9orf72 hypermethylation was associated with longer disease duration in FTD (β = 0.03, p = 0.007). Furthermore, C9orf72 hypermethylation was associated with smaller hexanucleotide repeat length (β = -16.69, p = 0.033). Finally, analysis of pedigrees with multiple mutation carriers demonstrated a significant association between C9orf72 methylation and family relatedness (p < 0.0001). C9orf72 hypermethylation is associated with prolonged disease in C9orf72 repeat expansion carriers with FTD. The attenuated clinical phenotype associated with C9orf72 hypermethylation suggests that slower clinical progression in FTD is associated with reduced expression of mutant C9orf72. These results support the hypothesis that expression of the hexanucleotide repeat expansion is associated with a toxic gain of function.
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