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Uncovering a novel SERPING1 pathogenic variant: insights into the aggregation of C1-INH in hereditary angioedema
被引:1
作者:

Jiang, Lingxi
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Res Unit Blindness Prevent Chinese Acad Med Sci 20, Chengdu 610072, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Dai, Chao
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Duan, Suyang
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Wang, Tingting
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Xie, Chunbao
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Zhang, Luhan
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Ye, Zimeng
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机构:
Univ Sydney, Sch Med, Camperdown, NSW 2006, Australia Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Ma, Xiumei
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China

Shi, Yi
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Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Ophthalmol, Chengdu 610072, Peoples R China
Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Res Unit Blindness Prevent Chinese Acad Med Sci 20, Chengdu 610072, Peoples R China
Sichuan Prov Peoples Hosp, Hlth Management Ctr, Chengdu 610072, Peoples R China Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
机构:
[1] Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Sichuan Prov Key Lab Human Dis Gene Study, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
[2] Univ Elect Sci & Technol China, Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Ctr Med Genet, Dept Lab Med, 32 First Ring Rd West 2, Chengdu 610072, Sichuan, Peoples R China
[3] Univ Elect Sci & Technol China, Sichuan Prov Peoples Hosp, Dept Ophthalmol, Chengdu 610072, Peoples R China
[4] Sichuan Acad Med Sci & Sichuan Prov Peoples Hosp, Res Unit Blindness Prevent Chinese Acad Med Sci 20, Chengdu 610072, Peoples R China
[5] Univ Sydney, Sch Med, Camperdown, NSW 2006, Australia
[6] Sichuan Prov Peoples Hosp, Hlth Management Ctr, Chengdu 610072, Peoples R China
关键词:
Apoptosis;
Ca2+ overload;
C1-INH;
Hereditary angioedema;
SERPING1 pathogenic variant;
ACTIVATED FACTOR-XII;
ACUTE ATTACKS;
INHIBITOR;
SYMPTOMS;
D O I:
10.1186/s13023-024-03306-7
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
Background 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. Results 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 Ca2+ 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. Conclusion Based on our findings, we propose that the detection of intracellular Ca2+ 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.
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CSL Behring Innovat GmbH, Marburg, Germany Penn State Univ, Dept Med & Pediat, Allergy Asthma & Immunol, Hershey, PA 17033 USA

Pawaskar, Dipti
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CSL Behring, King Of Prussia, PA USA
Janssen Res & Dev LLC, Spring House, PA USA Penn State Univ, Dept Med & Pediat, Allergy Asthma & Immunol, Hershey, PA 17033 USA

Jacobs, Iris
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CSL Behring, King Of Prussia, PA USA Penn State Univ, Dept Med & Pediat, Allergy Asthma & Immunol, Hershey, PA 17033 USA

Pragst, Ingo
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CSL Behring Innovat GmbH, Marburg, Germany Penn State Univ, Dept Med & Pediat, Allergy Asthma & Immunol, Hershey, PA 17033 USA

Doyle, Mittie K.
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CSL Behring, King Of Prussia, PA USA
Aro Biotherapeut, Philadelphia, PA USA Penn State Univ, Dept Med & Pediat, Allergy Asthma & Immunol, Hershey, PA 17033 USA
[10]
Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75
[J].
D'Eletto, Manuela
;
Rossin, Federica
;
Occhigrossi, Luca
;
Farrace, Maria Grazia
;
Faccenda, Danilo
;
Desai, Radha
;
Marchi, Saverio
;
Refolo, Giulia
;
Falasca, Laura
;
Antonioli, Manuela
;
Ciccosanti, Fabiola
;
Fimia, Gian Maria
;
Pinton, Paolo
;
Campanella, Michelangelo
;
Piacentini, Mauro
.
CELL REPORTS,
2018, 25 (13)
:3573-+

D'Eletto, Manuela
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Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Rossin, Federica
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Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Occhigrossi, Luca
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Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Farrace, Maria Grazia
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Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Faccenda, Danilo
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Univ London, Royal Vet Coll, Dept Comparat Biomed Sci, Royal Coll St, London NW1 0TU, England Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Desai, Radha
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Univ London, Royal Vet Coll, Dept Comparat Biomed Sci, Royal Coll St, London NW1 0TU, England Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

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Refolo, Giulia
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Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Falasca, Laura
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Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Antonioli, Manuela
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Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Ciccosanti, Fabiola
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Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Fimia, Gian Maria
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Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy
Univ Salento, Dept Biol & Environm Sci & Technol DiSTeBA, I-73100 Lecce, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

Pinton, Paolo
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Univ Ferrara, Lab Technol Adv Therapies LTTA, Sect Pathol Oncol & Expt Biol, Dept Morphol Surg & Expt Med, I-44122 Ferrara, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy

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Piacentini, Mauro
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Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy
Natl Inst Infect Dis IRCCS L Spallanzani, I-00149 Rome, Italy Univ Roma Tor Vergata, Dept Biol, I-00133 Rome, Italy