DNA hypermethylation of NOTCH2NLC in neuronal intranuclear inclusion disease: a case-control study.
DNA methylation
Epigenetics
NOTCH2NLC
Neuronal intranuclear inclusion disease
Journal
Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161
Informations de publication
Date de publication:
Nov 2022
Nov 2022
Historique:
received:
31
03
2022
accepted:
04
07
2022
revised:
27
05
2022
pubmed:
21
7
2022
medline:
14
10
2022
entrez:
20
7
2022
Statut:
ppublish
Résumé
GGC repeat expansions in NOTCH2NLC gene have been recently proposed to cause neuronal intranuclear inclusion disease (NIID) via prevailing gain-of-function mechanism (protein and RNA toxicity). Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of repeat-mediated disorders. In this study, using MethylTarget sequencing, we performed a quantitative analysis of the methylation status of 68 CpG sites located around the NOTCH2NLC promoter in 25 NIID patients and 25 age- and gender-matched healthy controls. We further explored the correlation of DNA methylation (DNAm) status with disease features and performed receiver operating characteristic (ROC) analysis. DNAm levels of GGC repeats and adjacent CpG islands were higher in the NIID patients than in controls, independent of gender and family history. DNAm levels at 4 CpG sites (CpG_207, CpG_421, GpG_473 and CpG_523) were negatively correlated with age at onset, and DNAm levels at 7 CpG sites (CpG_25, CpG_298, CpG_336, CpG_374, CpG_411, CpG_421 and CpG_473) were positively correlated with GGC repeats. NIID patients had concomitant system symptoms besides nervous system symptoms, and negative correlations between NOTCH2NLC DNAm levels and the number of multi-systemic involvement were observed in the study. The area under the ROC curve at NOTCH2NLC DNAm level reached to 0.733 for the best cutoff point of 0.012. Our findings suggested the aberrant DNAm status of the NOTCH2NLC promoter in NIID, and we explored the link between DNAm levels and disease features quantitatively for the first time, which may help to further explore pathogenic mechanism.
Sections du résumé
BACKGROUND
BACKGROUND
GGC repeat expansions in NOTCH2NLC gene have been recently proposed to cause neuronal intranuclear inclusion disease (NIID) via prevailing gain-of-function mechanism (protein and RNA toxicity). Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of repeat-mediated disorders.
METHODS
METHODS
In this study, using MethylTarget sequencing, we performed a quantitative analysis of the methylation status of 68 CpG sites located around the NOTCH2NLC promoter in 25 NIID patients and 25 age- and gender-matched healthy controls. We further explored the correlation of DNA methylation (DNAm) status with disease features and performed receiver operating characteristic (ROC) analysis.
RESULTS
RESULTS
DNAm levels of GGC repeats and adjacent CpG islands were higher in the NIID patients than in controls, independent of gender and family history. DNAm levels at 4 CpG sites (CpG_207, CpG_421, GpG_473 and CpG_523) were negatively correlated with age at onset, and DNAm levels at 7 CpG sites (CpG_25, CpG_298, CpG_336, CpG_374, CpG_411, CpG_421 and CpG_473) were positively correlated with GGC repeats. NIID patients had concomitant system symptoms besides nervous system symptoms, and negative correlations between NOTCH2NLC DNAm levels and the number of multi-systemic involvement were observed in the study. The area under the ROC curve at NOTCH2NLC DNAm level reached to 0.733 for the best cutoff point of 0.012.
CONCLUSIONS
CONCLUSIONS
Our findings suggested the aberrant DNAm status of the NOTCH2NLC promoter in NIID, and we explored the link between DNAm levels and disease features quantitatively for the first time, which may help to further explore pathogenic mechanism.
Identifiants
pubmed: 35857137
doi: 10.1007/s00415-022-11272-y
pii: 10.1007/s00415-022-11272-y
doi:
Substances chimiques
RNA
63231-63-0
DNA
9007-49-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6049-6057Subventions
Organisme : National Natural Science Foundation of China
ID : 81870889
Organisme : National Natural Science Foundation of China
ID : 82071258
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
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