C9orf72 Gene Expression in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
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Bulletin of Experimental Biology and Medicine, Vol. 169, No. 5, September, 2020 GENETICS
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C9orf72 Gene Expression in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
Yu. A. Shpilyukova, E. Yu. Fedotova, N. Yu. Abramycheva, I. A. Kochergin, I. V. Zakroyshchikova, M. N. Zakharova, and S. N. Illarioshkin Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 169, No. 5, pp. 604-607, May, 2020 Original article submitted February 4, 2020 We studied the expression of C9orf72 gene in pathologies associated with hexanucleotide repeats expansion in this gene: frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The study included 7 patients with hexanucleotide repeats expansion in the C9orf72 gene and 9 patients of the control group. The expression of C9orf72 mRNA was evaluated in blood leukocytes by real-time PCR. Methylation of CpG-sites in C9orf72 promotor region was evaluated by DNA sequencing after bisulfite conversion. A 2-fold decrease in the C9orf72 gene expression was found in patients with hexanucleotide repeats expansion in comparison with controls, though the difference did not reach statistical significance due to small sample size. The highest expression was shown for ALS in comparison with FTD and FTD-ALS phenotype. A trend to inverse correlation between C9orf72 mRNA level and promoter methylation of this gene as well as between mRNA level and age of disease onset was demonstrated. Key Words: С9orf72 gene; gene expression; amyotrophic lateral sclerosis; frontotemporal dementia Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with specific clinical features reflecting involvement of the brain cortex and peripheral motor neurons. It is known that up to 15% FTD patients have ALS symptoms and up to 50% ALS patients have clinical symptoms of FTD [10]. Due to significant clinical, genetic, and neuropathologic overlapping, these two diseases are considered as two extreme phenotypic variants of single FTD-ALS spectrum. C9orf72 gene mutation, one of the most frequent cause of the FTD and ALS in various populations, represents expansion of hexanucleotide repeats GGGGCC in the first intron of this gene. The frequency of this mutation in the C9orf72 gene in the Russian population according to our latest data is 14% in FTD patients and 4.3% in ALS patients, which is slightly higher than previously published data [1,3]. There are several hypotheses about the molecular pathogenesis of the neurodegenerative process in carriResearch Center of Neurology, Moscow, Russia. Address for correspondence: [email protected]. Yu. A. Shpilyukova
ers of expansion of hexanucleotide repeats; one of these attributes it to haploinsufficiency and reduced content of C9orf72 protein. It was shown that the decrease in C9orf72 gene expression could be related to both an increase in the number of hexanucleotide repeats and epigenetic modifications, in particular, DNA hypermethylation in the promoter region of this gene [7]. Besides haploinsuf
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