Role of genetic disorders in acute recurrent pancreatitis

Keim, Volker

doi:10.3748/wjg.14.1011

Cited by 28 publications

(33 citation statements)

References 21 publications

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“…It has been reported that mutation in the human equivalent Spink1 gene can lead to chronic pancreatitis (13). This report shows that pancreas-specific expression of the rat PSTI-I protein, which is similar but not identical to the mouse SPINK3 protein, was able to compensate for the absence of SPINK3 in Spink3 Ϫ/Ϫ mice and restore viability in Spink3 Ϫ/Ϫ /TgN(Psti1) mice.…”

Section: Discussionmentioning

confidence: 73%

“…It has been estimated that patients heterozygous for a SPINK1 mutation have a 20-to 40-fold increased risk of developing chronic pancreatitis (13,24). This risk may be as high as 500-fold in individuals with homozygous mutations (13).…”

Section: Discussionmentioning

confidence: 99%

“…This risk may be as high as 500-fold in individuals with homozygous mutations (13). The mechanism by which SPINK1 mutations predisposes one to chronic pancreatitis is not entirely clear but has been attributed to ultimate loss of function.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to PRSS1, which has been identified as a high-penetrance gene leading to chronic pancreatitis through gain-of-function mutations (2), SPINK1 appears to be an intermediate-penetrance gene in which the most common variant allele (N34S) increases pancreatitis susceptibility (2,13). Homozygote mutation at position 34 (N34S) confers a high-penetrance effect of SPINK1 on chronic pancreatitis (13,33).…”

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confidence: 99%

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Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Romac¹,

Ohmuraya

Bittner³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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RA. Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype. Am J Physiol Gastrointest Liver Physiol 298: G518 -G524, 2010. First published January 28, 2010; doi:10.1152/ajpgi.00431.2009.-Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene (Spink3 Ϫ/Ϫ ) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3 Ϫ/Ϫ mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3 ϩ/Ϫ heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3 ϩ/ϩ , Spink3 ϩ/Ϫ , and Spink3 Ϫ/Ϫ /TgN(Psti1) mice had similar survival rates, no Spink3 Ϫ/Ϫ mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.PSTI-I; pancreatitis; autophagy TRYPSIN IS SYNTHESIZED in the pancreas in the form of inactive trypsinogen and stored in zymogen granules within acinar cells. Pancreatic secretory trypsin inhibitor (PSTI) is an endogenous protein inhibitor of trypsin that is also present in zymogen granules and inhibits prematurely activated trypsin to protect the pancreas from possible damage (11). Serine protease inhibitor Kazal-type 1 (SPINK1) is the human homolog of PSTI and is expressed at high levels in the pancreas (7) representing 0.1-0.6% of total pancreatic protein (8) and 0.1-0.8% of the total protein in pancreatic juice (28). It has been estimated that the amount of trypsinogen exceeds the amount of trypsin inhibitor in the pancreas, and in humans it has been shown that SPINK1 mRNA levels are 1,000-fold lower than cationic trypsinogen (PRSS1) levels (14) raising the possib...

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Romac¹,

Ohmuraya

Bittner³

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Hereditary pancreatitis (HP) is an inherited form of chronic pancreatitis characterized by mutations within PRSS1, PRSS2, SPINK1, CFTR and CTRC genes [54,55] . PDAC is often a consequence of this condition [56,57] insomuch so resected pancreata from patients with HP frequently demonstrated PanIN-3 lesions (50%) [58] .…”

Section: Hereditary Pancreatitismentioning

confidence: 99%

Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer

Lami

Biagini

Galli

2014

WJGE

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Pancreatic cancer is a highly lethal disease with a genetic susceptibility and familial aggregation found in 3%-16% of patients. Early diagnosis remains the only hope for curative treatment and improvement of prognosis. This can be reached by the implementation of an intensive screening program, actually recommended for individuals at high-risk for pancreatic cancer development. The aim of this strategy is to identify premalignant precursors or asymptomatic pancreatic cancer lesions, curable by surgery. Endoscopic ultrasound (EUS) with or without fine needle aspiration (FNA) seems to be the most promising technique for early detection of pancreatic cancer. It has been described as a highly sensitive and accurate tool, especially for small and cystic lesions. Pancreatic intraepithelial neoplasia, a precursor lesion which is highly represented in highrisk individuals, seems to have characteristics chronic pancreatitis-like changes well detected by EUS. Many screening protocols have demonstrated high diagnostic yields for pancreatic pre-malignant lesions, allowing prophylactic pancreatectomies. However, it shows a high interobserver variety even among experienced endosonographers and a low sensitivity in case of chronic pancreatitis. Some new techniques such as contrast-enhanced harmonic EUS, computer-aided diagnostic techniques, confocal laser endomicroscopy miniprobe and the detection of DNA abnormalities or protein markers by FNA, promise improvement of the diagnostic yield of EUS. As the resolution of imaging improves and as our knowledge of precursor lesions grows, we believe that EUS could become the most suitable method to detect curable pancreatic neoplasms in correctly identified asymptomatic at-risk patients.© 2014 Baishideng Publishing Group Inc. All rights reserved. Key words: Endoscopic ultrasonography; Pancreatic cancer; SurveillanceCore tip: In the era of early diagnosis and screening programs, endoscopic ultrasound (EUS) represents the most promising tool able to identify pancreatic precursor neoplasms in high risk individuals. If compared to other imaging techniques, it is highly accurate to diagnose small pancreatic cancer and pre-malignant lesions, with very low rate of complications and limitations. Here are reported the current role of EUS in various international screening programs and its future possible developments.

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Epidemiology and Prospects for Prevention of Pancreatic Cancer

Jiao

2010

Pancreatic Cancer

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Role of genetic disorders in acute recurrent pancreatitis

Cited by 28 publications

References 21 publications

Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

Endoscopic ultrasonography for surveillance of individuals at high risk for pancreatic cancer

Epidemiology and Prospects for Prevention of Pancreatic Cancer

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