Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Teich, Niels; Rosendahl, Jonas; Tóth, Miklós; Mössner, Joachim; Sahin–Tóth, Miklós

doi:10.1002/humu.20343

Cited by 110 publications

(86 citation statements)

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“…Biochemical analysis of PRSS1 mutations revealed, for the two most common mutations, an increased trypsin activity. For the R122H mutation, increased trypsin activity is mediated by an increased stability, preventing physiologic autolysis, and for the N29I, mutation is related to enhanced trypsin auto-activation [31][32][33]. A similar clinical appearance is observed with SPINK1 mutations, which are also associated with hereditary chronic pancreatitis [34], even though the most frequently found N34S mutation does not influence anti-protease activity of SPINK1 [35].…”

Section: Influence Of Cigarette Smoke On Proteases and Anti-protease mentioning

confidence: 88%

Cigarette smoke-induced pancreatic damage—experimental data

Wittel

Hopt

Batra

2008

Langenbecks Arch Surg

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Section: Influence Of Cigarette Smoke On Proteases and Anti-protease mentioning

confidence: 88%

Cigarette smoke-induced pancreatic damage—experimental data

Wittel

Hopt

Batra

2008

Langenbecks Arch Surg

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“…However, the unusually high resistance of human cationic trypsin to autolysis in vitro has called into question the presumed protective role of trypsin autolysis and the proposed pathomechanism of the R122H mutation. Hereditary pancreatitis follows an autosomal dominant inheritance pattern with incomplete penetrance and variable disease expression, and it is typically characterized by early onset episodes of acute pancreatitis with frequent progression to chronic pancreatitis and an increased risk for pancreatic cancer (9,22). Besides mutation R122H, to date Ͼ20 other cationic trypsinogen variants have been identified in pancreatitis patients, but mutation R122H is responsible for the large majority of cases (Ϸ70%) (22).…”

Section: Discussionmentioning

confidence: 99%

Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: Identity with Rinderknecht's enzyme Y

Szmola

Sahin–Tóth

2007

Proc. Natl. Acad. Sci. U.S.A.

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145

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Digestive trypsins undergo proteolytic breakdown during their transit in the human alimentary tract, which has been assumed to occur through trypsin-mediated cleavages, termed autolysis. Autolysis was also postulated to play a protective role against pancreatitis by eliminating prematurely activated intrapancreatic trypsin. However, autolysis of human cationic trypsin is very slow in vitro, which is inconsistent with the documented intestinal trypsin degradation or a putative protective role. Here we report that degradation of human cationic trypsin is triggered by chymotrypsin C, which selectively cleaves the Leu 81 -Glu 82 peptide bond within the Ca 2؉ binding loop. Further degradation and inactivation of cationic trypsin is then achieved through tryptic cleavage of the Arg 122 -Val 123 peptide bond. Consequently, mutation of either Leu 81 or Arg 122 blocks chymotrypsin C-mediated trypsin degradation. Calcium affords protection against chymotrypsin C-mediated cleavage, with complete stabilization observed at 1 mM concentration. Chymotrypsin C is highly specific in promoting trypsin degradation, because chymotrypsin B1, chymotrypsin B2, elastase 2A, elastase 3A, or elastase 3B are ineffective. Chymotrypsin C also rapidly degrades all three human trypsinogen isoforms and appears identical to enzyme Y, the enigmatic trypsinogen-degrading activity described by Heinrich Rinderknecht in 1988. Taken together with previous observations, the results identify chymotrypsin C as a key regulator of activation and degradation of cationic trypsin. Thus, in the high Ca 2؉ environment of the duodenum, chymotrypsin C facilitates trypsinogen activation, whereas in the lower intestines, chymotrypsin C promotes trypsin degradation as a function of decreasing luminal Ca 2؉ concentrations. chronic pancreatitis ͉ digestive enzymes ͉ trypsinogen degradation

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“…The above notwithstanding, a loss of trypsin was also hypothesized to cause chronic pancreatitis, based upon the biochemical characterization of the R122C missense mutation. 17 However, as already pointed out by Teich et al, 8 no evidence exists to support this hypothesis from a genetic point of view, and clear 'loss of function' PRSS1 mutations (eg nonsense, splice site, or frameshift) have never been reported to cause the disease. In addition, although the E79K missense mutation was found to result in decreased autoactivation of cationic trypsinogen, E79K-trypsin proved to cause an increased transactivation of anionic trypsinogen.…”

Section: Introductionmentioning

confidence: 97%