Sichuan Provincial Key Laboratory for Human Disease Gene Study and the Center for Medical Genetics, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 32 The First Ring Road West 2, Chengdu, Sichuan, 610072, China.
Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610072, China.
Orphanet J Rare Dis. 2024 Sep 13;19(1):341. doi: 10.1186/s13023-024-03306-7.
Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by recurrent edema and a potentially fatal risk. Despite its severity, there is a notable lack of effective methods for predicting and preventing HAE attacks. This study aims to thoroughly investigate the underlying pathological mechanisms of HAE and identify potential biomarkers that could aid in its prediction and prevention.
In our investigation, we have discovered a novel pathogenic variant of the SERPING1 gene, specifically c.708T > G, in a Han family affected by HAE. Our observations indicate that this variant leads to an increase in the accumulation of C1-INH within the endoplasmic reticulum (ER), resulting in the upregulation of GRP75 protein expression. This cascade of events resulted in Ca overload, disruption of mitochondrial structure and function, and eventually triggered apoptosis. Using siRNA to knock down GRP75 mitigates cellular calcium overload and mitochondrial damage induced by the SERPING1 mutation.
Based on our findings, we propose that the detection of intracellular Ca concentration could serve as a valuable biomarker for predicting acute attacks of HAE in patients. This discovery holds significant implications for the development of more targeted and effective strategies in the management of HAE.
遗传性血管性水肿（HAE）是一种罕见的常染色体显性遗传疾病，其特征为反复发作的水肿和潜在的致命风险。尽管其严重程度显著，但目前缺乏有效的方法来预测和预防 HAE 发作。本研究旨在深入研究 HAE 的潜在病理机制，并确定可能有助于其预测和预防的潜在生物标志物。
在我们的研究中，我们在一个汉族 HAE 家族中发现了 SERPING1 基因的一种新的致病性变异，即 c.708T>G。我们的观察表明，这种变异导致 C1-INH 在内质网（ER）内的积累增加，从而导致 GRP75 蛋白表达上调。这一连串事件导致钙超载、线粒体结构和功能破坏，最终引发细胞凋亡。使用 siRNA 敲低 GRP75 可减轻 SERPING1 突变引起的细胞内钙超载和线粒体损伤。
基于我们的发现，我们提出细胞内 Ca 浓度的检测可以作为预测 HAE 患者急性发作的有价值的生物标志物。这一发现对于开发更有针对性和有效的 HAE 管理策略具有重要意义。
