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  • BMJ  (2)
  • Zhu, Min  (2)
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  • BMJ  (2)
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    Online Resource
    Online Resource
    Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease
    BMJ ; 2019
    In:  Journal of Medical Genetics Vol. 56, No. 11 ( 2019-11), p. 758-764
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 56, No. 11 ( 2019-11), p. 758-764
    Abstract: Neuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients. Methods Fifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases. Results Our patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases. Conclusion Our findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2019-106268
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 2009590-9
    SSG: 12
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Genetic origin of sporadic cases and RNA toxicity in neuronal intranuclear inclusion disease
    BMJ ; 2022
    In:  Journal of Medical Genetics Vol. 59, No. 5 ( 2022-05), p. 462-469
    Details
    In: Journal of Medical Genetics, BMJ, Vol. 59, No. 5 ( 2022-05), p. 462-469
    Abstract: GGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID. Methods Multiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared. Results In two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier. Conclusion Our study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.
    Type of Medium: Online Resource
    ISSN: 0022-2593 , 1468-6244
    URL: Article
    DOI: 10.1136/jmedgenet-2020-107649
    RVK:
    WA 15000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2009590-9
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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