Article Text
Statistics from Altmetric.com
We read the recent publication of Schnúr et al1 with great interest, in which the authors proposed that a subset of human cationic trypsinogen (PRSS1) variants caused chronic pancreatitis by inducing misfolding and endoplasmic reticulum (ER) stress rather than increased intrapancreatic trypsin activity. PRSS1 variants that promote premature trypsinogen activation are the strongest known risk factors for chronic pancreatitis; often associated with autosomal-dominant hereditary pancreatitis. ER-stress causing PRSS1 variants, on the other hand, have been mostly found in sporadic disease with no family history suggesting these variants might confer lower risk.
To refute this notion, here we report a hereditary pancreatitis family of Hungarian origin carrying the heterozygous c.311T>C (p.L104P) PRSS1 variant which was recently demonstrated to induce misfolding and ER stress.2 The index patient, his mother and first cousin developed recurrent acute or chronic pancreatitis in this family (figure 1). Sanger sequencing was carried out on genomic DNA of all 12 live family members after informed consent was obtained. All exons of the PRSS1, SPINK1, CTRC and CPA1 genes and exons 4, 10 and 11 of the CFTR gene were sequenced in all affected subjects. In all unaffected family members PRSS1 exon 3 was sequenced. In the unaffected children of the index patient's cousin CTRC exons 2 and 3 were also analysed. All three affected members were heterozygous for the p.L104P PRSS1 variant. Interestingly, both children of the index patient and two children of the first cousin were unaffected despite carrying the pathogenic variant. While this observation may indicate lower penetrance of the mutation, we note that age of onset was delayed in the index patient (36 years) and his mother (32 years) suggesting that some of the children are likely to develop pancreatitis at a later age. All affected individuals were smokers and all quit at the time of diagnosis. Alcohol consumption was clinically not significant. Pancreatolithiasis was documented in all three affected subjects and removal of the intraductal stones prevented further acute attacks. All relevant clinical findings in the three affected family members are summarised in table 1.
In addition to the PRSS1 p.L104P variant, the index patient's affected cousin also carried a heterozygous c.180C>T (p.G60=) variant in the CTRC gene. This variant increases the risk for chronic pancreatitis about twofold and may have been responsible for the earlier onset of pancreatitis (18 years) and more severe exocrine insufficiency in this subject relative to the other two affected family members (table 1). No other pathogenic variants were identified in the tested susceptibility genes in the affected family members.
Our observations indicate that misfolding PRSS1 variants may act as strong risk factors for chronic pancreatitis and may be associated with autosomal-dominant hereditary pancreatitis. Furthermore, the findings argue that ER stress is a highly relevant pathological mechanism in chronic pancreatitis and alleviating pancreatic ER stress should be a therapeutic target.
Acknowledgments
The authors thank Ákos Pap, Tamás Takács, Emese Horváth and András Nagy for providing clinical data, helpful discussions and advice.
Footnotes
MS-T and PH contributed equally
Contributors Study concept and design: BCN, AVP, MS-T and PH. 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: PH and MS-T. Administrative, technical or material support: all authors. Study supervision: BCN, MS-T and PH. Final approval of manuscript as submitted: all authors. Guarantors of the article: BCN and PH.
Funding Hungarian Scientific Research Fund (K116634); Momentum Grant of the Hungarian Academy of Sciences (LP2014-10/2014); and Gazdaságfejlesztési és Innovációs Operatív Program GINOP-2.3.2-15-2016-00015 (to PH); National Institutes of Health R01 DK058088 (to MS-T).
Competing interests None declared.
Ethics approval Scientific and Research Ethics Committee of the Medical Research Council of Hungary (22254-1/2012/EKU).
Provenance and peer review Not commissioned; internally peer reviewed.