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.
Department of Cell Biology, Center for Stem Cell and Medicine, Naval Medical University, Shanghai, 200433, China.
Adv Sci (Weinh). 2024 Oct;11(38):e2402550. doi: 10.1002/advs.202402550. Epub 2024 Aug 9.
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.
慢性胰腺炎（CP）是一种复杂的疾病，其发生涉及遗传和环境因素。通过对一个中国青少年 CP 患者的三核苷酸外显子组测序，发现了一个新的 SEC16A 移码变异。随后对 1061 名中国 CP 患者和 1196 名对照者的 SEC16A 基因进行靶向下一代测序，发现患者中罕见非同义 SEC16A 变异的等位基因频率更高（4.90% vs 2.93%；优势比[OR]，1.71；95%置信区间[CI]，1.26-2.33）。在法国队列中也观察到了类似的富集（OR，2.74；95% CI，1.67-4.50），并且在生物银行荟萃分析中也观察到了类似的富集（OR，1.16；95% CI，1.04-1.31）。值得注意的是，携带 SEC16A 变异的中国 CP 患者的中位发病年龄比不携带变异的患者早 5 年（40.0 岁 vs 45.0 岁；p = 0.012）。使用三个 CRISPR/Cas9 编辑的 HEK293T 细胞系进行的功能研究表明，功能丧失性 SEC16A 变异会破坏衣壳蛋白复合物 II（COPII）的形成，阻碍分泌蛋白囊泡的运输，并由于蛋白过载而诱导内质网（ER）应激。与 Sec16a 相比，Sec16a 小鼠表现出酶原分泌受损和 ER 应激加重，进一步生成了 Sec16a 小鼠。在 Cerulein 刺激的胰腺炎模型中，与野生型小鼠相比，Sec16a 小鼠显示出更高的胰腺炎症和纤维化程度。这些发现提示了一种新的致病机制，可能导致 CP。
