Epigenetic study of C9orf72 in FTD and ALS patients including family with identical twins

ZHENGRUI, XI; INNOCENZO RAINERO; ELISA RUBINO; LORENZO PINESSI; AMALIA BRUNI; RAFFAELE MALETTA; BENEDETTA NACMIAS; SANDRO SORBI; DANIELA GALIMBERTI; EZEQUIEL SURACE; MARIA TARTAGLIA; MARKA VAN BLITTERSWIJK; ROSA RADEMAKERS; YANA YUNUSOVA; JANICE ROBERTSON; PETER ST. GEORGE-HYSLOP; LORNE ZINMAN ZINMAN; EKATERINA ROGAEVA

Vancouver

Congreso; 9th International Conference on Frontotemporal Dementias; 2014

University of British Columbia, Canada

C9orf72 transcription is reduced in expansion carriers, suggesting haploinsufficiency as one of the disease mechanisms. We investigated DNA methylation of the CpG-island (5?of the repeat) in ALS, FTD and control samples. Methylation level was variable between the samples (any of the 26 investigated CpGs could be methylated). Hypermethylation (>4 CpGs) was expansion-specific (it occurred only in carriers of >50 repeats), but not syndrome-specific (ALS vs. FTD). Intriguingly, we detected a high methylation level in only 36% of carriers; however down-regulation of C9orf72 expression was demonstrated in all previously published carriers. Therefore, additional DNA region(s) could be subject to methylation (e.g. the repeat itself). The diversity of C9orf72-phenotypes implies the existence of modifying factors, which could be investigated in monozygotic twins. Despite the identical genetic background, twins from a Canadian family have been ALS-discordant for ~5 years, while the first signs of FTD were recently observed only in the twin unaffected by ALS. Based on the analysis of blood DNA, the twins have no methylation at the CpG-island and a similar range of repeat size (800-1350 repeats); however, expansion size in brain DNA could be different from blood. Cumulatively, the identical genetic background of the twins, similarities in both methylation level and repeat size, rather argue in favor of an environmental vs. genetic phenotype modifier in this family. Of note, both twins have had similar environmental exposures; except the twin with ALS was a smoker and had a head-trauma. The results of another unique C9orf72 family will also be presented