Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Topic: Brain proteins, microglia and lab models

Results In our primary cohort, higher methylation levels were observed in patients with a C9orf72 repeat expansion than in patients without this expansion (p = 1.7e-13) or in control subjects (p = 3.3e-07). Moreover, we discovered that an increase in methylation levels was associated with a decrease in total C9orf72 transcript levels (p = 5.5e-05). These findings aligned with our observation that C9orf72 expansion carriers had lower expression levels of total C9orf72 transcripts than patients lacking this expansion (p = 3.7e-07) or control subjects (p = 9.1e-05). We also detected an elevation of transcripts containing intron 1a (upstream of the repeat) in patients carrying a C9orf72 repeat expansion compared to (disease) controls (p ≤ 0.01), an indication of abortive transcripts and/or a switch in transcription start site usage. Furthermore, smaller repeat lengths were detected in currently unaffected individuals than in affected individuals (p = 8.9e-04) and they were associated with an earlier age at collection (p = 0.008). Conclusions In blood from C9orf72 expansion carriers, we found elevated methylation levels, reduced expression levels, and unstable expansions that tend to contract in successive generations, arguing against anticipation.

Key findings

• Results In our primary cohort, higher methylation levels were observed in patients with a C9orf72 repeat expansion than in patients without this expansion (p = 1.7e-13) or in control subjects (p = 3.3e-07).
• Moreover, we discovered that an increase in methylation levels was associated with a decrease in total C9orf72 transcript levels (p = 5.5e-05).
• These findings aligned with our observation that C9orf72 expansion carriers had lower expression levels of total C9orf72 transcripts than patients lacking this expansion (p = 3.7e-07) or control subjects (p = 9.1e-05).
• We also detected an elevation of transcripts containing intron 1a (upstream of the repeat) in patients carrying a C9orf72 repeat expansion compared to (disease) controls (p ≤ 0.01), an indication of abortive transcripts and/or a switch in transcription start site usage.
• Furthermore, smaller repeat lengths were detected in currently unaffected individuals than in affected individuals (p = 8.9e-04) and they were associated with an earlier age at collection (p = 0.008).

Why it matters

In blood from C9orf72 expansion carriers, this study found elevated methylation, reduced C9orf72 expression, and repeat expansions that tended to contract across generations. These are biological observations about a genetic cause of dementia and do not provide a treatment, cure, or prevention.

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Study details

• Participants75
• Evidence strengthModerate

Read the original

• DOI: 10.1186/s13024-020-0359-8
• PubMed: 32000838
• Original source →
• Free full text: Molecular Neurodegeneration →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{jackson2020-32000838,
  author  = {Jackson, J. L. and Finch, N. A. and Baker, M. C. and Kachergus, J. M. and DeJesus-Hernandez, M. and Pereira, K. and Christopher, E. and Prudencio, M. and others},
  title   = {{Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers}},
  journal = {Molecular neurodegeneration},
  year    = {2020},
  doi     = {10.1186/s13024-020-0359-8},
  pmid    = {32000838},
  url     = {https://doi.org/10.1186/s13024-020-0359-8}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia
• Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS Neuron · 2013-02-12 · usefulness score 57/100 · Lewy body dementia
• RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia Proceedings of the National Academy of Sciences of the United States of America · 2013-11-18 · usefulness score 57/100 · Lewy body dementia
• C9orf72 nucleotide repeat structures initiate molecular cascades of disease Nature · 2014-03-05 · usefulness score 57/100 · Lewy body dementia
• Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS Acta neuropathologica · 2013-10-16 · usefulness score 56/100 · Lewy body dementia
• Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins Acta neuropathologica · 2013-10-17 · usefulness score 54/100 · Lewy body dementia

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