Evaluation of methylation status of the 5’-promoter region of C9orf72 gene in Russian patients with neurodegenerative diseases

Background. Hexanucleotide repeat expansion in the C9orf72 gene is the most significant cause of a large number of neurodegenerative diseases: frontotemporal degeneration (FTD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), etc. Several studies have shown the relationship with the neurodegenerative process for full (>40 GGGGCC copies) and intermediate (13–20) repeats expansion. Methylation of the C9orf72 gene can play an important role in the pathogenesis of FTD and ALS, but the mechanism has not been sufficiently studied.

The objective is to investigate the status of methylation of the 5’-promotor region of the C9orf72 gene in patients with neurodegenerative disorders having full or intermediate expansion of GGGGCC-repeats.

Materials and methods. We investigated the methylation status of the 5’-promoter region of full C9orf72 expansions in FTD/ALS patients (n = 12), of intermediate expansions in Parkinson’s disease patients (n = 8) and of non-expanded alleles in healthy controls (n = 8). Methylation status was determined via sequencing of amplified fragments of bisulfite-converted DNA.

Results. We identified two cases (sibling) with the hypermethylation of the 5’-promoter region in the full C9orf72 expansions group. Patient A. (65 years old, male) had an atypical ALS presentation: an onset with head tremor, a long duration of ALS symptoms (9 years at this time), and cognitive impairments with a temporal lobes atrophy. The patient’s sister had a similar clinical phenotype. There were no cases of the promoter hypermethylation in the intermediate and control groups.

Conclusion. This is the first data on the 5’-promoter region C9orf72 gene methylation in Russian population. The frequency of the promoter methylation in this group was 9.1 % that consistent with previous studies in other populations. Atypical clinical presentation may indicate a modifying effect of methylation in this area on the ALS phenotype.

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