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The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter

(2016) MOLECULAR PSYCHIATRY. 21(8). p.1112-1124
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Abstract
Pathological expansion of a G(4)C(2) repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G(4)C(2) expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G(4)C(2) expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G(4)C(2) expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P = 0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G(4)C(2) (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G(4)C(2) size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.
Keywords
AMYOTROPHIC-LATERAL-SCLEROSIS, FRONTOTEMPORAL LOBAR DEGENERATION, GGGGCC, HEXANUCLEOTIDE REPEAT, FRAGILE X-SYNDROME, RNA FOCI, PATHOLOGICAL, FEATURES, FRIEDREICH ATAXIA, CPG-ISLAND, NEURODEGENERATIVE DISORDERS, CLINICAL CHARACTERISTICS

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Chicago
Gijselinck, I, S Van Mossevelde, J van der Zee, Anne Sieben, S Engelborghs, Jan De Bleecker, A Ivanoiu, et al. 2016. “The C9orf72 Repeat Size Correlates with Onset Age of Disease, DNA Methylation and Transcriptional Downregulation of the Promoter.” Molecular Psychiatry 21 (8): 1112–1124.
APA
Gijselinck, I., Van Mossevelde, S., van der Zee, J., Sieben, A., Engelborghs, S., De Bleecker, J., Ivanoiu, A., et al. (2016). The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. MOLECULAR PSYCHIATRY, 21(8), 1112–1124.
Vancouver
1.
Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Engelborghs S, De Bleecker J, et al. The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. MOLECULAR PSYCHIATRY. 2016;21(8):1112–24.
MLA
Gijselinck, I et al. “The C9orf72 Repeat Size Correlates with Onset Age of Disease, DNA Methylation and Transcriptional Downregulation of the Promoter.” MOLECULAR PSYCHIATRY 21.8 (2016): 1112–1124. Print.
@article{8547500,
  abstract     = {Pathological expansion of a G(4)C(2) repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G(4)C(2) expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G(4)C(2) expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6\% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G(4)C(2) expansion size with onset age (P{\textlangle}0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P{\textlangle}0.0001) and brain (P{\textlangle}0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P = 0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P{\textlangle}0.0001) and a decrease of C9orf72 promoter activity (P{\textlangle}0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G(4)C(2) (P{\textlangle}0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G(4)C(2) size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.},
  author       = {Gijselinck, I and Van Mossevelde, S and van der Zee, J and Sieben, Anne and Engelborghs, S and De Bleecker, Jan and Ivanoiu, A and Deryck, O and Edbauer, D and Zhang, M and Heeman, B and Baumer, V and Van den Broeck, M and Mattheijssens, M and Peeters, K and Rogaeva, E and De Jonghe, P and Cras, P and Martin, J-J and de Deyn, PP and Cruts, M and Van Broeckhoven, C and BELNEU consortium, the and Dermaut, Bart and Santens, Patrick and Van Langenhove, Tim},
  issn         = {1359-4184},
  journal      = {MOLECULAR PSYCHIATRY},
  language     = {eng},
  number       = {8},
  pages        = {1112--1124},
  title        = {The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter},
  url          = {http://dx.doi.org/10.1038/mp.2015.159},
  volume       = {21},
  year         = {2016},
}

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