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We have read with interest the recent publication of Hegyi and Sahin-Tóth1 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-Tóth study, will not predispose …
Contributors J-HL, AB and EM performed the functional assay. J-MC, ZL, Z-SL and CF designed the study. J-MC drafted the paper. DNC critically revised the manuscript. All authors analysed the data, contributed to revision of the manuscript and approved the final manuscript.
Funding J-HL, a joint PhD student between the Changhai Hospital and INSERM U1078, was in receipt of a 20-month scholarship from the China Scholarship Council (No 201706580018). Support for this study came from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association des Pancréatites Chroniques Héréditaires, and the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, France; the National Natural Science Foundation of China (81470884 and 81770636 (to ZL) and 81873588 (to ZSL)), the Chang Jiang Scholars Program of Ministry of Education (Q2015190 (to ZL)), and the Scientific Innovation Program of Shanghai Municipal Education Committee (to ZL), China.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
Patient consent for publication Not required.
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