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Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier

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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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Acknowledgments

We thank the patients and patients’ families who made this research possible. We acknowledge Drs. J. Q. Trojanowski and V. M.-Y. Lee and the Center for Neurodegenerative Disease Research for their support. This study was supported in part by a grant from the Judith & Jean Pape Adams Foundation and by the National Institutes of Health (K08AG039510, P30AG10124, P01AG017586, P01AG032953, P50AG005681). EBL is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award.

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  1. Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 605B Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA, 19104, USA

    Jenny Russ, Elaine Y. Liu, Kathryn Wu & Edward B. Lee

  2. Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Donald Neal, EunRan Suh, David J. Irwin, Elisabeth M. Wood & Vivianna M. Van Deerlin

  3. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    David J. Irwin, Corey T. McMillan, Lauren Elman, Leo McCluskey & Murray Grossman

  4. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

    Matthew B. Harms & Nigel J. Cairns

  5. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sharon X. Xie

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Russ, J., Liu, E.Y., Wu, K. et al. Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129, 39–52 (2015). https://doi.org/10.1007/s00401-014-1365-0

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