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Rare mutations in the autophagy‐regulating gene AMBRA1 contribute to human neural tube defects
Author(s) -
Ye Jianhong,
Tong Youli,
Lv Jiashun,
Peng Rui,
Chen Shuxia,
Kuang Lele,
Su Ke,
Zheng Yufang,
Zhang Ting,
Zhang Feng,
Jin Li,
Yang Xueyan,
Wang Hongyan
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24028
Subject(s) - neural tube , biology , autophagy , gene knockdown , neurulation , exencephaly , morpholino , regulator , microbiology and biotechnology , genetics , gene , embryo , embryogenesis , fetus , apoptosis , pregnancy , gastrulation , teratology
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. Autophagy and beclin 1 regulator 1 (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 messenger RNA (mRNA) to overexpress or rescue ambra1a ‐morpholino oligos (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.