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Clinical Research

Genetics of Pancreatitis: A Guide for Clinicians

Witt H.

Author affiliations

Department of Pediatrics, Technische Universität München (TUM), Munich, Germany

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Dig Dis 2010;28:702–708

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Article / Publication Details

First-Page Preview
Abstract of Clinical Research

Published online: April 27, 2011
Issue release date: April 2011

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: https://www.karger.com/DDI

Abstract

It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15–40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25–30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.

© 2011 S. Karger AG, Basel


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    External Resources

Article / Publication Details

First-Page Preview
Abstract of Clinical Research

Published online: April 27, 2011
Issue release date: April 2011

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 0

ISSN: 0257-2753 (Print)
eISSN: 1421-9875 (Online)

For additional information: https://www.karger.com/DDI


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