Background 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.
- GGC repeated expansion
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JD and MG contributed equally.
Contributors DJH and ZXW conceived the research, designed studies and supervised the project; JWD, MLG and JXY designed and carried out experiments and analysed data; SY, MZ, PF, XFY, JZ, FL, JB, WS, YNH, YY, DJH and ZXW contributed to the clinical diagnosis and biopsy of NIID patients; YM, PDL, YNS and JH analysed the LRS data; JWD, DJH and ZXW wrote and edited the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the National Natural Science Foundation of China under Grant No. 81460199, 81870996 and 81571219.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The research was approved by the ethics committee of Peking University First Hospital and Peking University People’s Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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