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Mutations in AMBRA1 aggravate β-thalassemia by impairing autophagy-mediated clearance of free α-globin.
Blood ( IF 21.0 ) Pub Date : 2024-12-18 , DOI: 10.1182/blood.2023022688 Yong Long,Qianqian Zhang,Ling Ling,Yuan Zhuang,Xiaolei Wei,Haoyang Huang,Zhanping Lu,Yushan Huang,Xianming Chen,Yuhua Ye,Xiaoqin Feng,Haokun Hao Zhang,Binbin Huang,Yueyan Huang,Yidan Liang,Mingyan Fang,Yukio Nakamura,Bin Lin,Xinhua Zhang,Daru Lu,Xin Jin,Xiangmin Xu
Blood ( IF 21.0 ) Pub Date : 2024-12-18 , DOI: 10.1182/blood.2023022688 Yong Long,Qianqian Zhang,Ling Ling,Yuan Zhuang,Xiaolei Wei,Haoyang Huang,Zhanping Lu,Yushan Huang,Xianming Chen,Yuhua Ye,Xiaoqin Feng,Haokun Hao Zhang,Binbin Huang,Yueyan Huang,Yidan Liang,Mingyan Fang,Yukio Nakamura,Bin Lin,Xinhua Zhang,Daru Lu,Xin Jin,Xiangmin Xu
Accumulation of free α-globin is a critical factor in the pathogenesis of β-thalassemia. Autophagy plays a crucial role in clearing toxic free α-globin, thereby reducing disease severity. However, the impact of natural mutations in autophagy-related genes (ATGs) on the phenotypic variability of β-thalassemia remains unclear. In this study, we systematically investigated the relationship between variants in ATGs and disease phenotypes in a cohort of 1,022 patients with β-thalassemia, identifying four missense mutations in the autophagy and beclin 1 regulator 1 (AMBRA1) gene. Disruption of the Ambra1 gene in β-thalassemic mice was found to reduce autophagic clearance of α-globin in red blood cell precursors, exacerbating disease phenotypes. Functional characterization of the AMBRA1 gene and these mutations in patient-derived CD34+ cells, edited HUDEP-2 cells, and engineered HUDEP-2 β-thalassemic cells confirmed that AMBRA1 facilitates the autophagic clearance of free α-globin in human erythroid cells. Functional studies demonstrated that AMBRA1 missense mutants destabilize ULK1 protein, inhibit LC3 lipidation, and subsequently hinder autophagic flux, leading to increased α-globin deposition. Additionally, these mutations were associated with erythrotoxic effects in vitro, including increased intracellular reactive oxygen species levels, higher apoptosis rates, and impaired erythroid differentiation and maturation. This study sheds light on the molecular association between mutations in ATGs and the exacerbation of β-thalassemia, highlighting the potential role of the AMBRA1 gene as a promising diagnostic and therapeutic target for β-hemoglobinopathies.
更新日期：2024-12-18
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