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Most unambiguous loss-of-function CPA1 mutations are unlikely to predispose to chronic pancreatitis
  1. Jin-Huan Lin1,2,
  2. Arnaud Boulling1,
  3. Emmanuelle Masson1,3,
  4. David N Cooper4,
  5. Zhao-Shen Li2,
  6. Claude Férec1,3,
  7. Zhuan Liao2,
  8. Jian-Min Chen1
  1. 1EFS, Univ Brest, Inserm, UMR 1078, GGB, Brest, France
  2. 2Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China
  3. 3CHU Brest, Service de Génétique, Brest, France
  4. 4Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK
  1. Correspondence to Dr Zhuan Liao, Department of Gastroenterology Changhai Hospital, The Second Military Medical University Shanghai China ; liaozhuan{at} and Dr Jian-Min Chen, INSERM UMR1078 – EFS – UBO, Brest 29238, France; jian-min.chen{at}

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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 …

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