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Through trio exome sequencing, a <jats:italic>de novo SEC16A<\/jats:italic> frameshift variant in a Chinese teenage CP patient is identified. Subsequent targeted next\u2010generation sequencing of the <jats:italic>SEC16A<\/jats:italic> gene in 1,061 Chinese CP patients and 1,196 controls reveals a higher allele frequency of rare nonsynonymous <jats:italic>SEC16A<\/jats:italic> variants in patients (4.90%\u00a0vs 2.93%; odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26\u20132.33). Similar enrichments are noted in a French cohort (OR, 2.74; 95% CI, 1.67\u20134.50) and in a biobank meta\u2010analysis (OR, 1.16; 95% CI, 1.04\u20131.31). Notably, Chinese CP patients with <jats:italic>SEC16A<\/jats:italic> variants exhibit a median onset age 5 years earlier than those without (40.0\u00a0vs 45.0; <jats:italic>p<\/jats:italic>\u00a0=\u00a00.012). Functional studies using three CRISPR\/Cas9\u2010edited HEK293T cell lines show that loss\u2010of\u2010function <jats:italic>SEC16A<\/jats:italic> variants disrupt coat protein complex II (COPII) formation, impede secretory protein vesicles trafficking, and induce endoplasmic reticulum (ER) stress due to protein overload. <jats:italic>Sec16a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice, which demonstrate impaired zymogen secretion and exacerbated ER stress compared to <jats:italic>Sec16a<\/jats:italic><jats:sup>+\/+<\/jats:sup>, are further generated. In cerulein\u2010stimulated pancreatitis models, <jats:italic>Sec16a<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice display heightened pancreatic inflammation and fibrosis compared to wild\u2010type mice. These findings implicate a novel pathogenic mechanism predisposing to CP.<\/jats:p>","DOI":"10.1002\/advs.202402550","type":"journal-article","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T07:29:25Z","timestamp":1723188565000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<i>SEC16A<\/i> Variants Predispose to Chronic Pancreatitis by Impairing ER\u2010to\u2010Golgi Transport and Inducing ER Stress"],"prefix":"10.1002","volume":"11","author":[{"given":"Min\u2010Jun","family":"Wang","sequence":"first","affiliation":[{"name":"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"},{"name":"Department of Cell Biology Center for Stem Cell and Medicine Naval Medical University  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Medical Devices Changhai Hospital National Key Laboratory of Immunity and Inflammation Naval Medical University  Shanghai 200433 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li\u2010Juan","family":"Wang","sequence":"additional","affiliation":[{"name":"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 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