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. ORCID: https://orcid.org/0000-0002-8943-8484, Férec, Claude, Li, Zhao‐Shen, Chen, Jian‐Min, Zou, Wen‐Bin and Liao, Zhuan 2024. SEC16A variants predispose to chronic pancreatitis by impairing ER‐to‐Golgi Transport and inducing ER stress. Advanced Science 11 (38) , 2402550. 10.1002/advs.202402550

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley Open Access
ISSN:	2198-3844
Date of First Compliant Deposit:	12 August 2024
Last Modified:	04 Nov 2024 14:38
URI:	https://orca.cardiff.ac.uk/id/eprint/171309

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