We have read with interest the recent publication of Hegyi and Sahin-Toth1 reporting that chronic pancreatitis (CP)-predisposing CPA1 mutations function through the misfolding pathway rather than through loss of CPA1 protein/activity. Herein, we explore an additional insight gleaned from this study beyond those discussed in an accompanying Editorial.2 In the original study reporting the association of CPA1 variants with CP, all unambiguous loss-of-function (LoF) variants (eg, nonsense mutations) were lumped together with missense mutations that functionally impaired the CPA1 protein.3 However, unlike missense mutations, unambiguous LoF variants often result in transcripts that contain premature termination codons (PTC) and are thus prone to nonsense-mediated RNA decay (NMD). NMD detects and degrades PTC-containing transcripts, thereby preventing the accumulation of truncated proteins.4 5 This implies that most unambiguous LoF CPA1 variants would not be able to elicit endoplasmic reticulum (ER) stress and hence, in light of the Hegyi and Sahin-Toth study, will not predispose …

中文翻译：

---

大多数明确的功能丧失 CPA1 突变不太可能导致慢性胰腺炎

我们饶有兴趣地阅读了 Hegyi 和 Sahin-Toth1 最近发表的文章，他们报道了慢性胰腺炎 (CP) 诱发的 CPA1 突变通过错误折叠途径而不是通过 CPA1 蛋白/活性的丧失起作用。在此，我们探索了从本研究中收集的额外见解，超出了随附社论中讨论的内容。 2 在报告 CPA1 变异与 CP 关联的原始研究中，所有明确的功能丧失 (LoF) 变异（例如，无义突变）与功能受损 CPA1 蛋白的错义突变混为一谈。3 然而，与错义突变不同，明确的 LoF 变体通常会导致转录本包含过早终止密码子 (PTC)，因此容易发生无义介导的 RNA 衰变 (NMD)。NMD 检测并降解含 PTC 的转录本，