| First Author | Wang MJ | Year | 2024 |
| Journal | Adv Sci (Weinh) | Volume | 11 |
| Issue | 38 | Pages | e2402550 |
| PubMed ID | 39119875 | Mgi Jnum | J:359007 |
| Mgi Id | MGI:7779689 | Doi | 10.1002/advs.202402550 |
| Citation | Wang MJ, et al. (2024) SEC16A Variants Predispose to Chronic Pancreatitis by Impairing ER-to-Golgi Transport and Inducing ER Stress. Adv Sci (Weinh) 11(38):e2402550 |
| abstractText | 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. |
