<i>C9ORF72</i>
            transcription in a frontotemporal dementia case with two expanded alleles

Cooper‐Knock, Johnathan; Higginbottom, Adrian; Connor-Robson, Natalie; Bayatti, Nadhim; Bury, Joanna J.; Kirby, Janine; Ninkina, Natalia; Buchman, Vladimir L.; Shaw, Pamela J.

doi:10.1212/01.wnl.0000435295.41974.2e

Cited by 27 publications

(25 citation statements)

References 8 publications

(10 reference statements)

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“…The possibility that this model pertains to C9orf72 fALS patients has led to efforts to identify protein-binding partners of the sense and antisense foci generated from the expanded G 4 C 2 repeat domain of C9orf72. Candidates identified to date include ADARB2 (62), hnRNP-H, and SF2 (59,61), though the consequence of this binding is presently unclear. The C9orf72 expansions might compromise cellular viability via mechanisms other than sequestering transcription factors.…”

Section: Figure 2 Pathogenic Mechanisms Associated With Hexanucleotimentioning

confidence: 99%

Emerging mechanisms of molecular pathology in ALS

Peters¹,

Ghasemi²,

Brown³

2015

J. Clin. Invest.

242

142

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Section: Figure 2 Pathogenic Mechanisms Associated With Hexanucleotimentioning

confidence: 99%

Emerging mechanisms of molecular pathology in ALS

Peters¹,

Ghasemi²,

Brown³

2015

J. Clin. Invest.

242

142

View full text Add to dashboard Cite

“…In contrast, nonsense and missense C9orf72 mutations were not found in a large ALS cohort [29]. Moreover, individuals homozygous for the C9orf72 mutation are phenotypically similar to heterozygous carriers, which argues against a loss of function mechanism [14, 24]. Experimental data are conflicting regarding C9orf72 haploinsufficiency, as reduction of C9orf72 in mice with antisense oligonucleotides does not result in a neurodegenerative phenotype in mice while knockdown of the C9orf72 homolog in zebrafish results in motor neuron axonal degeneration [8, 32].…”

Section: Discussionmentioning

confidence: 99%

C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD

et al. 2014

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Hexanucleotide repeat expansions of C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal degeneration. The mutation is associated with reduced C9orf72 expression and the accumulation of potentially toxic RNA and protein aggregates. CpG methylation is known to protect the genome against unstable DNA elements and to stably silence inappropriate gene expression. Using bisulfite cloning and restriction enzyme-based methylation assays on DNA from human brain and peripheral blood, we observed CpG hyper-methylation involving the C9orf72 promoter in cis to the repeat expansion mutation in approximately one-third of C9orf72 repeat expansion mutation carriers. Promoter hypermethylation of mutant C9orf72 was associated with transcriptional silencing of C9orf72 in patient-derived lymphoblast cell lines, resulting in reduced accumulation of intronic C9orf72 RNA and reduced numbers of RNA foci. Furthermore, demethylation of mutant C9orf72 with 5-aza-deoxycytidine resulted in increased vulnerability of mutant cells to oxidative and autophagic stress. Promoter hypermethylation of repeat expansion carriers was also associated with reduced accumulation of RNA foci and dipeptide repeat protein aggregates in human brains. These results indicate that C9orf72 promoter hypermethylation prevents downstream molecular aberrations associated with the hexanucleotide repeat expansion, suggesting that epigenetic silencing of the mutant C9orf72 allele may represent a protective counter-regulatory response to hexanucleotide repeat expansion.

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“…Further supporting the nonpathogenicity of smaller repeat alleles is the report of a rare case with an allele with approximately 50 repeats and an expanded allele (> 2,000 repeats); this patient had gene expression levels similar to that of heterozygous expansion carriers with 1 allele in the normal range and to a lymphoblastoid cell line with a 45-repeat allele that did not have a decreased gene expression [99]. Of note, unequivocal evidence indicates that repeat expansion in the atypical range might be genetically unstable and expand upon subsequent generations [35,68,71]; therefore, it may be considered analogous to Fragile X, i.e., a "pre-mutation" [35].…”

Section: Discussionmentioning

confidence: 80%

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

et al. 2018

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Background: European studies identified the C9orf72 repeat expansion as the most frequent genetic alteration in patients with Huntington disease (HD)-like phenotypes but negative HD genetic testing. Objective: To investigate C9orf72 repeat expansion frequency in individuals tested for HD in a North American tertiary referral laboratory. Methods: Three hundred and seventy-three cases (115 positive and 258 negative for HD) were evaluated by genotyping PCR, with follow-up Southern blot and 5′ repeat methylation status assessment by combined repeat-primed and methylation-specific PCR in a subset. Results: Three cases (all HD-negative) tested positive: 2 had > 2,000 repeats and were methylated, 1 had 80–100 repeats and was unmethylated. Two cases (1 HD-positive and 1 HD-negative) had intermediate alleles (20–29 repeats) and were unmethylated. The remaining 368 cases were negative (< 20 repeats). C9orf72 repeat expansion was absent in patients with HD and was identified in a small subset (1.2%) of patients with negative HD genetic testing. Conclusion: These findings suggest that C9orf72 repeat expansion does not coexist with HTT repeat expansion and that C9orf72 repeat expansion testing is unnecessary for patients with HD. In addition, C9orf72 evaluation may be considered for individuals negative for HD genetic testing. Similar to in previous studies, methylation of C9orf72 repeat expansion was limited to large expansions.

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C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles

Cited by 27 publications

References 8 publications

Emerging mechanisms of molecular pathology in ALS

Emerging mechanisms of molecular pathology in ALS

C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD

C9orf72 Repeat Expansion Frequency among Patients with Huntington Disease Genetic Testing

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