The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

Grocock, Christopher; Rebours, Vinciane; Delhaye, Myriam; Andrén‐Sandberg, Åke; Weiß, Frank Ulrich; Mountford, Roger; Harcus, M.; Niemczyck, E.; Vitone, Louis; Dodd, Susie; Jørgensen, Maiken Thyregod; Ammann, Rudolf W.; Muckadell, O. Schaffalitzky de; Butler, Jane; Burgess, Phillip; Kerr, Bronwyn; Charnley, Richard; Sutton, Robert; Raraty, Michael; Devière, Jacques; Whitcomb, David C.; Neoptolemos, John P.; Lévy, Philippe; Lerch, Markus M.; Greenhalf, William

doi:10.1136/gut.2009.186817

Cited by 49 publications

(22 citation statements)

References 21 publications

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“…Mutation A16V is associated with variable disease penetrance and was identified not only in hereditary pancreatitis families but also in sporadic cases with no family history, suggesting a weaker biochemical phenotype (27,28). The mutation is found in ϳ3% of PRSS1 mutation-positive pancreatitis cases, although a recent study from Denmark reported higher regional occurrence (29).…”

Section: Autoactivation Of Cationic Trypsinogen Mutants In Presence Omentioning

confidence: 86%

Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Szabó

Sahin–Tóth

2012

Journal of Biological Chemistry

141

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Background: Hereditary pancreatitis is caused by mutations in human cationic trypsinogen. Chymotrypsin C (CTRC) is a proteolytic regulator of trypsinogen activation. Results: Clinically relevant trypsinogen mutations increase autoactivation in the presence of CTRC. Conclusion: Pathological trypsinogen activation in hereditary pancreatitis is dependent on CTRC. Significance: Therapeutic suppression of trypsinogen autoactivation is warranted in carriers of pancreatitis-causing mutations.

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Section: Autoactivation Of Cationic Trypsinogen Mutants In Presence Omentioning

confidence: 86%

Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Szabó

Sahin–Tóth

2012

Journal of Biological Chemistry

141

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“…The p. R122H mutation is the most common one, followed by the p.N29I mutation. The p.A16V (c.47C>T) mutation (Grocock et al 2010) is the third most common one, but has not been reported in Japanese subjects.…”

Section: Prss1 Mutationsmentioning

confidence: 99%

Genetics of Pancreatitis: The 2014 Update

Masamune

2014

Tohoku J. Exp. Med.

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Chronic pancreatitis is a progressive inflammatory disease in which pancreatic secretory parenchyma is destroyed and replaced by fibrous tissue, eventually leading to malnutrition and diabetes. Alcohol is the leading cause in Western countries, but genetic factors are also implicated. Since the identification of mutations in the cationic trypsinogen (PRSS1) gene as a cause of hereditary pancreatitis in 1996, we have seen great progress in our understanding of the genetics of pancreatitis. It has been established that mutations in the genes related to the activation and inactivation of trypsin(ogen) such as PRSS1, serine protease inhibitor Kazal type 1 (SPINK1) and chymotrypsin C (CTRC) genes are associated with pancreatitis. In 2013, carboxypeptidase A1 (CPA1) was identified as a novel pancreatitis susceptibility gene. Endoplasmic reticulum stress in pancreatic acinar cells resulting from the mis-folding of mutated pancreatic enzymes has been shown to act as a novel mechanism underlying the susceptibility to pancreatitis. In Japan, the nationwide survey revealed 171 patients (96 males and 75 females) with hereditary pancreatitis in 59 families based on the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer criteria. Because about 30% of families with hereditary pancreatitis do not carry mutations in any of the known pancreatitis susceptibility genes, other yet unidentified genes might be involved. Next generation sequencers can perform billions of sequencing reactions with a read length of 150-250 nucleotides. Comprehensive analysis using next generation sequencers will be a promising strategy to identify novel pancreatitis-associated genes and further clarify the pathogenesis of pancreatitis.

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“…Much more is presently known about genetic risk factors. The most important ones are mutations in the cationic trypsinogen gene [2,13,14,15] which were the first identified cause of hereditary pancreatitis. In contrast to mutations in the cationic trypsin gene, a G191R mutation in the anionic trypsin gene (PRSS2) was shown to have a protective effect [16].…”

Section: Chronic Pancreatitismentioning

confidence: 99%

Environmental Risk Factors for Chronic Pancreatitis and Pancreatic Cancer

Nitsche

Simon

Weiss

et al. 2011

Dig Dis

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Chronic pancreatitis has long been thought to be mainly associated with immoderate alcohol consumption. The observation that only ∼10% of heavy drinkers develop chronic pancreatitis not only suggests that other environmental factors, such as tobacco smoke, are potent additional risk factors, but also that the genetic component of pancreatitis is more common than previously presumed. Either disease-causing or protective traits have been indentified for mutations in different trypsinogen genes, the gene for the trypsin inhibitor SPINK1, chymotrypsinogen C, and the cystic fibrosis transmembane conductance regulator (CFTR). Other factors that have been proposed to contribute to pancreatitis are obesity, diets high in animal protein and fat, as well as antioxidant deficiencies. For the development of pancreatic cancer, preexisting chronic pancreatitis, more prominently hereditary pancreatitis, is a risk factor. The data on environmental risk factors for pancreatic cancer are, with the notable exception of tobacco smoke, either sparse, unconfirmed or controversial. Obesity appears to increase the risk of pancreatic cancer in the West but not in Japan. Diets high in processed or red meat, diets low in fruits and vegetables, phytochemicals such as lycopene and flavonols, have been proposed and refuted as risk or protective factors in different trials. The best established and single most important risk factor for cancer as well as pancreatitis and the one to clearly avoid is tobacco smoke.

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The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families

Abstract: Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.

Cited by 49 publications

References 21 publications

Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Genetics of Pancreatitis: The 2014 Update

Environmental Risk Factors for Chronic Pancreatitis and Pancreatic Cancer

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