Mutations of Gly277 in -related chronic pancreatitis: clinical clues for misfolding aetiology.
(2026) Gut — (2026)
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Sahin-Tóth, Miklós 
- Abstract
- We have been elated to see the recent flurry of publications by Gut on chronic pancreatitis (CP) associated with mutations of the pancreatic digestive enzyme carboxypeptidase A1 (CPA1).1–4 These studies confirmed that CPA1 gene variants are strong risk factors for CP and exert their pathogenic effect through promoting enzyme misfolding and endoplasmic reticulum (ER) stress, although the exact mechanism of pancreatic inflammation has remained unclear. Through the functional analysis of 63 CPA1 variants in cell culture studies, we previously established that pathogenic variants caused diminished secretion (<10% wild type) and markedly upregulated heat shock protein family A member 5 (HSPA5, encoding the immunoglobulin heavy chain binding protein, BiP) mRNA expression, a marker of ER stress, as exemplified by the pathogenic reference variant p.Asn256Lys.1 4 The CPA1 N256K mouse model carrying the p.Asn256Lys mutation in the native mouse Cpa1 gene developed progressive CP with acinar atrophy, fibrosis, macrophage infiltration, acinar-to-ductal metaplasia and plasma amylase elevation.5 6 Despite the increased mechanistic understanding of the pathogenic role of CPA1 variants, specific clinical characteristics of misfolding-induced CP have not been reported to date. [...]
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Citations
Zheng, Y., Scheers, I., Sándor, M., Yi, G., & Sahin-Tóth, M. (2026). Mutations of Gly277 in -related chronic pancreatitis: clinical clues for misfolding aetiology. Gut. Accepted/in-press. https://doi.org/10.1136/gutjnl-2025-337733 (Original work published 2026)