<i>SEC16A</i> Variants Predispose to Chronic Pancreatitis by Impairing ER‐to‐Golgi Transport and Inducing ER Stress

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<sup>+/-</sup> mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a<sup>+/+</sup>, are further generated. In cerulein-stimulated pancreatitis models, Sec16a<sup>+/-</sup> 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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Publication Details

Journal
Advanced Science
Published
2024-08-09
DOI
https://doi.org/10.1002/advs.202402550
Citations
9
Primary Topic
Pancreatitis Pathology and Treatment
Type
article
Field-Weighted Citation Impact
5.15

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article

SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER‐to‐Golgi Transport and Inducing ER Stress

Vinciane Rebours, Xin‐Ying Tang, Shun‐Jiang Deng, Liang‐Hao Hu et al.
9 citations
Advanced Science
Pancreatitis Pathology and Treatment
5.15
article

SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER‐to‐Golgi Transport and Inducing ER Stress

Vinciane Rebours, Xin‐Ying Tang, Shun‐Jiang Deng, Liang‐Hao Hu, Zhuan Liao, D.N. Cooper, Claude Férec, Yuan‐Chen Wang, Emmanuelle Masson, Yang‐Yang Qian, Dong Yu, Jian‐Min Chen, Lijuan Wang, Zhao‐Shen Li, Min‐Jun Wang, Wen‐Bin Zou, Yahui Wang, Lei Wang
article en
9 citations

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<sup>+/-</sup> mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to Sec16a<sup>+/+</sup>, are further generated. In cerulein-stimulated pancreatitis models, Sec16a<sup>+/-</sup> mice display heightened pancreatic inflammation and fibrosis compared to wild-type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.

Advanced ScienceVol. 11(38)
Inserm (FR), Université de Bretagne Occidentale (FR), Second Military Medical University (CN), École nationale d'ingénieurs de Brest (FR), Université Paris Cité (FR), Hôpital Beaujon (FR), Assistance Publique – Hôpitaux de Paris (FR), Changhai Hospital (CN), Centre Hospitalier Régional Universitaire de Brest (FR), Eastern Hepatobiliary Surgery Hospital (CN), Génétique, Génomique Fonctionnelle et Biotechnologies (FR), Cardiff University (GB)
Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China
Openalex Percentile: Top 4%
Pancreatitis Pathology and Treatment
5.15
DOIOpen Access PDFOpenAlex
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