英国剑桥大学Stefan J. Marciniak课题组的最新研究提出了α -1抗胰蛋白酶缺乏症患者肝脏SERPINA1体细胞逃逸变异的选择。2025年3月10日，国际知名学术期刊《自然—遗传学》发表了这一成果。

研究小组分析了来自α-1抗胰蛋白酶（A1AT）缺乏或血色素沉着症的遗传性CLD患者的肝脏体细胞变异。该团队发现编码A1AT的基因SERPINA1的体细胞变异在A1AT缺陷中被强烈选择，这是趋同进化的证据。获得的SERPINA1变异位于A1AT的羧基末端，导致截断。在体外和体内，c端截断变异体减少了疾病相关的Z-A1AT聚合物的积累和内质网的破坏，支持C端结构域交换机制。因此，在A1AT缺乏症中选择了来自一种有害生殖系变异的体细胞逃逸变异，这表明功能性体细胞变异在CLD中是疾病特异性的，并指向疾病相关机制。

据介绍，随着年龄的增长，体细胞变异在非恶性组织中积累。导致肝细胞克隆优势的功能变异在获得性慢性肝病（CLD）患者的肝脏中积累。来自不同病因的体细胞变异是否在CLD中普遍存在尚不清楚。

附：英文原文

Title: Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency

Author: Brzozowska, Natalia, Wu, Lily Y. D., Khodzhaeva, Vera, Griffiths, William J., Duckworth, Adam, Jung, Hyunchul, Coorens, Tim H. H., Hooks, Yvette, Chambers, Joseph E., Campbell, Peter J., Marciniak, Stefan J., Hoare, Matthew

Issue&Volume: 2025-03-10

Abstract: Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.

DOI: 10.1038/s41588-025-02125-1

Source: https://www.nature.com/articles/s41588-025-02125-1