McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, McCluskey L, Elman L, Van Deerlin V, Lee EB. C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence. Neurology. 2015 Apr 21;84(16):1622-30. Epub 2015 Mar 20 PubMed.

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  1. This interesting study is particularly notable for the way it integrates methylation analysis with a number of other data types, including clinical symptoms, neuropathology, and neuroimaging. Although the study includes a relatively small number of patients, the authors' success contrasts with similar studies attempting to correlate C9ORF72 repeat length (as measured by Southern blotting) with disease severity and supports their methodology, but also suggests that future work should integrate region-specific analysis of C9ORF72 repeat length with methylation status. Overall this data is supportive of other work suggesting that C9ORF72 repeat expansions produce gain-of-function toxicity—hypermethylation-mediated transcriptional silencing, which reduces disease severity measured clinically, pathologically, or using imaging. In a previous study the authors have also observed correlation between hypermethylation and reduction in RNA foci and dipeptide repeat proteins derived from the repeat sequence.

    View all comments by Johnathan Cooper-Knock

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