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Letter
Functional predictors of pathogenicity of missense CPA1 variants in chronic pancreatitis
  1. Máté Sándor,
  2. Miklós Sahin-Tóth
  1. Department of Surgery, University of California Los Angeles, Los Angeles, California, USA
  1. Correspondence to Miklós Sahin-Tóth, Department of Surgery, University of California Los Angeles, Los Angeles, CA 90095, USA; msahintoth{at}mednet.ucla.edu

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We read with great interest the recent article by Zhu et al,1 demonstrating that misfolding of pancreatic lipase due to an inborn mutation causes chronic pancreatitis (CP). Variants in the CPA1 gene, encoding procarboxypeptidase A1, can elicit CP by the same mechanism, however, not all variants are alike, and correct prediction of benign versus pathogenic behaviour has been challenging.

In 2013, rare heterozygous variants in CPA1 were identified in multiple cohorts of CP cases.2 Functional analysis indicated that patients preferentially carried loss-of-function CPA1 variants, most of which were poorly secreted or not secreted at all from transfected cells. When examined in aggregate, loss-of-function CPA1 variants were significantly over-represented in cases versus controls, with higher prevalence in early-onset disease. Individually, however, only three loss-of-function missense variants (p.N256K, p.Y308H, p.R382W) showed significant enrichment in CP. Disease association could not be ascertained for the majority of variants due to their ultra-low frequency.

Variant p.N256K was characterised functionally in detail using HEK 293T cells, AR42J cells and a knock-in mouse model.2–4 The experiments revealed that p.N256K triggered CP in mice and caused loss of proenzyme secretion, intracellular retention and increased endoplasmic reticulum (ER) stress in cellular models and mice. The findings suggested that CP develops in …

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Footnotes

  • Contributors MS-T contributed to study concept and design. MS contributed to experiments. All authors contributed to acquisition, analysis or interpretation of data. MS-T contributed to drafting of the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content. MS-T obtained funding. All authors received administrative, technical or material support. MS-T contributed to study supervision. All authors contributed to final approval of manuscript as submitted . MS-T is the guarantor of the article.

  • Funding This study was supported by the National Institutes of Health (NIH) grants R01 DK058088, R01 DK117809 and R01 DK082412 to MS-T.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.