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Novel p.K374E variant of CPA1 causes misfolding-induced hereditary pancreatitis with autosomal dominant inheritance
  1. Balázs Csaba Németh1,2,
  2. Anna Orekhova3,
  3. Wenying Zhang4,5,
  4. Shannon A Nortman5,
  5. Tyler Thompson6,
  6. Péter Hegyi2,7,
  7. Maisam Abu-El-Haija4,6
  1. 1 First Department of Medicine, University of Szeged, Szeged, Hungary
  2. 2 Momentum Gastroenterology Multidisciplinary Research Group, Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary
  3. 3 Department of Molecular and Cell Biology, Henry M Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, USA
  4. 4 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  5. 5 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  6. 6 Division of Pediatric Gastroenterology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  7. 7 Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
  1. Correspondence to Dr Balázs Csaba Németh, University of Szeged First Department of Medicine, Szeged, Korányi fasor 8-10., H-6720, Hungary; nemeth.balazs{at}med.u-szeged.hu

https://doi.org/10.1136/gutjnl-2019-318751

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    We read the publication written by Lin et al 1 with great interest. The authors suggest that the majority of functionally defective carboxypeptidase A1 (CPA1) mutations can elicit reduced expression due to nonsense-mediated decay (NMD) and therefore, only a small subset of the earlier reported CPA1 variants2 will predispose to chronic pancreatitis (CP) via the misfolding-dependent pathway.3 This paper seemingly offered an explanation for the earlier finding of Wu et al 4 where the authors reported no association with CP of rare functionally defective CPA1 variants in a large Chinese cohort.

    However, it was earlier reported that functionally impaired variants of the CPA1 gene were strongly associated with sporadic cases of non-alcoholic, early-onset CP in European, Indian and Japanese populations.5 In addition, members of two Polish families carrying the p.S282P variant of the CPA1 gene developed hereditary CP.6 Protein misfolding and consequent endoplasmic reticulum (ER) stress were described as a potential disease mechanism of hereditary pancreatitis caused by loss-of-function variants of CPA1 and PRSS1 genes.3 6 7 Recently, the finding that a knock-in mouse model carrying the misfolding-causing p.N256K CPA1 variant developed CP confirmed the significance of the misfolding-dependent pathway in the disease mechanism8 and revealed a novel opportunity for in vivo …

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    Footnotes

    • Contributors Study concept and design: BCN and MAEH. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: all authors. Obtained funding: BCN, PH, MAEH, and funds by the Molecular Genetics Laboratory at Cincinnati Children’s Hospital Medical Center. Administrative, technical or material support: all authors. Study supervision: BCN and MAEH. Final approval of manuscript as submitted: all authors. Guarantors of the article: BCN and MAEH.

    • Funding Hungarian National Research, Development and Innovation Fund (FK124632 to BCN and K116634 to PH); Momentum Grant of the Hungarian Academy of Sciences (LP2014-10/2014 to PH); Economic Development and Innovation Operative Programme Grant of the National Research, Development and Innovation Office (GINOP 2.3.2-15-2016-00048 to PH); National Institutes of Health (R43 DK 105640-01 to MAEH).

    • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    • Competing interests None declared.

    • Ethics approval This study was reviewed and approved by the Cincinnati Children’s Hospital Medical Center (CCHMC) Institutional Review Board (IRB number 2018-7699).

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Patient consent for publication Obtained.