期刊
NATURE GENETICS
卷 51, 期 8, 页码 1215-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-019-0459-y
关键词
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资金
- Japan Agency for Medical Research and Development (AMED) [JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18kk0205001, JP18ek0109348, JP18md0107059, JP18ek0109284, JP18dm020715, JP18dm0107059, JP18am0101108]
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP19659225, JP17K15639, JP17K16132, JP17K15630, JP17H06994, JP24591257, JP15K09312, JP16K07464]
- MEXT [26119002, 26117002]
- Takeda Science Foundation
- Daiwa Securities Health Foundation
- Termo Foundation for Life Sciences and Arts
- Grants-in-Aid for Scientific Research [26119002] Funding Source: KAKEN
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes antemortem diagnosis difficult(1-8), but skin biopsy enables its antemortem diagnosis(9-12). The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
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