In:
Digestive Diseases, S. Karger AG, Vol. 28, No. 6 ( 2010), p. 702-708
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 〈 i 〉 (PRSS1) 〈 /i 〉 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 〈 i 〉 (PRSS2) 〈 /i 〉 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 〈 i 〉 SPINK1 〈 /i 〉 , 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 〈 i 〉 CTRC 〈 /i 〉 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 〈 i 〉 CTRC 〈 /i 〉 predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between 〈 i 〉 CFTR 〈 /i 〉 , 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 〈 i 〉 CFTR 〈 /i 〉 mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a 〈 i 〉 CFTR 〈 /i 〉 alteration and a 〈 i 〉 PRSS1, SPINK1, 〈 /i 〉 or CTRC variant 〈 i 〉 , 〈 /i 〉 respectively.
Type of Medium:
Online Resource
ISSN:
0257-2753
,
1421-9875
Language:
English
Publisher:
S. Karger AG
Publication Date:
2010
detail.hit.zdb_id:
1482221-0
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