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.
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
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping