PUBLICATION
Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects
- Authors
- Ye, J., Tong, Y., Lv, J., Peng, R., Chen, S., Kuang, L., Su, K., Zheng, Y., Zhang, T., Zhang, F., Jin, L., Yang, X., Wang, H.
- ID
- ZDB-PUB-200426-25
- Date
- 2020
- Source
- Human Mutation 41(8): 1383-1393 (Journal)
- Registered Authors
- Keywords
- AMBRA1, Neural tube defects, autophagy, rare mutations, trehalose, zebrafish
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Animals
- Autophagy
- Case-Control Studies
- Child, Preschool
- China
- Female
- Gene Knockdown Techniques
- HEK293 Cells
- Humans
- Infant
- Male
- Mutation, Missense
- Neural Tube Defects/genetics*
- Zebrafish
- PubMed
- 32333458 Full text @ Hum. Mutat.
Citation
Ye, J., Tong, Y., Lv, J., Peng, R., Chen, S., Kuang, L., Su, K., Zheng, Y., Zhang, T., Zhang, F., Jin, L., Yang, X., Wang, H. (2020) Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects. Human Mutation. 41(8):1383-1393.
Abstract
Neural tube defects (NTDs) are severe congenital malformations caused by failed neural tube closure. Recently, autophagy is revealed to play a vital role in neuroepithelium development and neurulation. Ambra1 is a crucial regulator of autophagy initiation, and its deficiency in mice leads to exencephaly and/or spina bifida. However, the genetic contribution of AMBRA1 to the etiology of human NTDs remains unknown. In this study, we identified five rare missense mutations of AMBRA1 in 352 NTDs cases, which were absent in 224 matched controls. Western blotting and fluorescence puncta counting for MAP1LC3A/LC3 in HEK293T cells suggested that four of the mutations (AMBRA1 p.Thr80Met, p.Leu274Phe, p.Ser743Phe, and p.Met884Val) affected autophagy initiation to various extents. Furthermore, these four mutations also displayed loss-of-function effects compared with wild-type AMBRA1 when we injected mRNA to overexpress or rescue ambra1a-MO knockdown in zebrafish. It is intriguing that trehalose, a natural disaccharide, could rescue ambra1a-MO knockdown in a dose-dependent manner independently or together with AMBRA1 mRNA. Taken together, our findings suggest that rare mutations of the autophagy regulator gene AMBRA1 may contribute to the etiology of human neural tube defects, and trehalose is a promising treatment for a subset of NTDs caused by autophagy impairment. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping