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SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress.
Wang, Min-Jun; Wang, Yuan-Chen; Masson, Emmanuelle; Wang, Ya-Hui; Yu, Dong; Qian, Yang-Yang; Tang, Xin-Ying; Deng, Shun-Jiang; Hu, Liang-Hao; Wang, Lei; Wang, Li-Juan; Rebours, Vinciane; Cooper, David N; Férec, Claude; Li, Zhao-Shen; Chen, Jian-Min; Zou, Wen-Bin; Liao, Zhuan.
Afiliación
  • Wang MJ; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Wang YC; Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University, Shanghai, 200433, China.
  • Masson E; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Wang YH; Inserm, EFS, UMR 1078, GGB, Univ Brest, Brest, F-29200, France.
  • Yu D; Service de Génétique Médicale et de Biologie de la Reproduction, CHRU Brest, Brest, F-29200, France.
  • Qian YY; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Tang XY; Center for Translational Medicine, Naval Medical University, Shanghai, 200433, China.
  • Deng SJ; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Hu LH; Department of Prevention and Health Care, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200438, China.
  • Wang L; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Wang LJ; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Rebours V; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Cooper DN; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Férec C; Pancreatology and Digestive Oncology Department, Beaujon Hospital, APHP - Clichy, Université Paris Cité, Paris, 92110, France.
  • Li ZS; Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
  • Chen JM; Inserm, EFS, UMR 1078, GGB, Univ Brest, Brest, F-29200, France.
  • Zou WB; Department of Gastroenterology, Shanghai Institute of Pancreatic Diseases, Shanghai Key Laboratory of Nautical Medicine and Translation of Drugs and Medical Devices, Changhai Hospital, National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, 200433, China.
  • Liao Z; Inserm, EFS, UMR 1078, GGB, Univ Brest, Brest, F-29200, France.
Adv Sci (Weinh) ; : e2402550, 2024 Aug 09.
Article en En | MEDLINE | ID: mdl-39119875
ABSTRACT
Chronic pancreatitis (CP) is a complex disease with genetic and environmental factors at play. Through trio exome sequencing, a de novo SEC16A frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next-generation sequencing of the SEC16A gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous SEC16A variants in patients (4.90% vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26-2.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67-4.50) and in a biobank meta-analysis (OR, 1.16; 95% CI, 1.04-1.31). Notably, Chinese CP patients with SEC16A variants exhibit a median onset age 5 years earlier than those without (40.0 vs 45.0; p = 0.012). Functional studies using three CRISPR/Cas9-edited HEK293T cell lines show that loss-of-function SEC16A variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. Sec16a+/- mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a+/+, are further generated. In cerulein-stimulated pancreatitis models, Sec16a+/- mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Adv Sci (Weinh) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Adv Sci (Weinh) Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Alemania