2. Academic Validation
  3. Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects

Rare mutations in the autophagy-regulating gene AMBRA1 contribute to human neural tube defects

  • Hum Mutat. 2020 Aug;41(8):1383-1393. doi: 10.1002/humu.24028.
Jianhong Ye 1 2,  Youli Tong 2,  Jiashun Lv 2,  Rui Peng 3,  Shuxia Chen 2,  Lele Kuang 2 4,  Ke Su 2,  Yufang Zheng 1 3 5,  Ting Zhang 6,  Feng Zhang 1 3 7,  Li Jin 2,  Xueyan Yang 2,  Hongyan Wang 1 3 7
Affiliations

Affiliations

  • 1 Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, China.
  • 2 The MOE Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China.
  • 3 Key Laboratory of Reproduction Regulation of NPFPC, Institute of Reproduction and Development, Fudan University, Shanghai, China.
  • 4 Department of Assisted Reproduction, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
  • 5 Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai, China.
  • 6 Beijing Municipal Key Laboratory of Child Development & Nutriomics, The Capital Institute of Pediatrics, Beijing, China.
  • 7 Children's Hospital of Fudan University, Shanghai, China.
PMID: 32333458 DOI: 10.1002/humu.24028
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.

Keywords

AMBRA1; autophagy; neural tube defects; rare mutations; trehalose; zebrafish.

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