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NUS1 Variants Cause Lennox-Gastaut Syndrome Related to Unfolded Protein Reaction Activation.
- Source :
- Molecular Neurobiology; Nov2024, Vol. 61 Issue 11, p8518-8530, 13p
- Publication Year :
- 2024
-
Abstract
- NUS1 encodes the Nogo-B receptor, a critical regulator for unfolded protein reaction (UPR) signaling. Although several loss-of-function variants of NUS1 have been identified in patients with developmental and epileptic encephalopathy (DEE), the role of the NUS1 variant in Lennox-Gastaut syndrome (LGS), a severe child-onset DEE, remains unknown. In this study, we identified two de novo variants of NUS1, a missense variant (c.868 C > T/p.R290C) and a splice site variant (c.792-2 A > G), in two unrelated LGS patients using trio-based whole-exome sequencing performed in a cohort of 165 LGS patients. Both variants were absent in the gnomAD population and showed a significantly higher observed number of variants than expected genome-wide. The R290C variant was predicted to damage NUS1 and decrease its protein stability. The c.792-2 A > G variant caused premature termination of the protein. Knockdown of NUS1 activated the UPR pathway, resulting in apoptosis of HEK293T cells. Supplementing cells with expression of wild-type NUS1, but not the mutant (R290C), rescued UPR activation and apoptosis in NUS1 knockdown cells. Compared to wild-type Drosophila, seizure-like behaviors and excitability in projection neurons were significantly increased in Tango14 (homolog of human NUS1) knockdown and Tango14<superscript>R290C/+</superscript> knock-in Drosophila. Additionally, abnormal development and a small body size were observed in both mutants. Activated UPR signaling was also detected in both mutants. Thus, NUS1 is a causative gene for LGS with dominant inheritance. The pathogenicity of these variants is related to the UPR signaling activation, which may be a common pathogenic mechanism of DEE. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08937648
- Volume :
- 61
- Issue :
- 11
- Database :
- Complementary Index
- Journal :
- Molecular Neurobiology
- Publication Type :
- Academic Journal
- Accession number :
- 180429344
- Full Text :
- https://doi.org/10.1007/s12035-024-04123-6