Hereditary pancreatitis and mutations of the cationic trypsinogen gene

O’Reilly, Derek; Kingsnorth, Andrew

doi:10.1046/j.1365-2168.2000.01495.x

Cited by 14 publications

(12 citation statements)

References 47 publications

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“…In human beings, a relationship between the PRSS1 gene mutations and the onset of pancreatitis has been established by many investigations. 21,30,41,42 Thus, it is possible that differences in primary structure or expression of the Prss1 gene are responsible for strain differences. Although we found one single-nucleotide polymorphism (SNP) in exon 4 that resulted in substitution of glutamic acid with lysine at amino-acid position 190 in JF1 mice, this mutation was not observed in the PRSS1 gene of human patients, suggesting that the coding region of the Prss1 gene is not related to the susceptibility to pancreatitis among these strains.…”

Section: Discussionmentioning

confidence: 99%

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

Wang

Ohmuraya

Suyama

et al. 2010

Laboratory Investigation

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To analyze susceptibility to acute pancreatitis, five mouse strains including Japanese Fancy Mouse 1 (JF1), C57BL/6J, BALB/c, CBA/J, and C3H/HeJ were treated with either a cholecystokinin analog, cerulein, or a choline-deficient, ethioninesupplemented (CDE) diet. The severity of acute pancreatitis induced by cerulein was highest in C3H/HeJ and CBA/J, moderate in BALB/c, and mildest in C57BL/6J and JF1. Basal protein expression levels of the serine protease inhibitor, Kazal type 3 (Spink3) were higher in JF1 and C57BL/6J mice than those of the other three strains under normal feeding conditions. After treatment with cerulein, expression level of Spink3 increased remarkably in JF1 and mildly in C57BL/6J, BALB/c, CBA/J, and C3H/HeJ strains. Increased proteinase, serine, 1 (Prss1) protein expression accompanied by increased trypsin activity with cerulein treatment was observed in susceptible strains such as CBA/J and C3H/HeJ. Similar results were obtained with a CDE diet. In the 3 kb Spink3 promoter region, 92 or 8 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively, whereas in the Prss1 promoter region 39 or 46 nucleotide changes were found in JF1 or C3H vs C57BL/6J, respectively. These results suggest that regulation of Prss1 and Spink3 expression is involved in the susceptibility to experimentally induced pancreatitis. The JF1 strain, which is derived from the Japanese wild mouse, will be useful to examine new mechanisms that may not be found in other laboratory mouse strains. Over 450 inbred strains of mice have been described, 1 providing a wealth of different genotypes and phenotypes for studying human diseases. Actually, the use of various breeding strategies in combination with positional cloning and positional candidate gene approach has led to the discovery of many genes that underlie human disease. 2 The Japanese wild mouse, belonging to Mus musculus molossinus, has several genetic characteristics clearly distinguishable from the European wild mouse, derived from M.m. domesticus. These subspecies were separated about one million years ago and about 1% of their genome sequences are different. [3][4][5][6][7][8] Therefore, strains MSM/Ms 9 and Japanese Fancy Mouse 1 (JF1), 10 which were established from M.m. molossinus, are powerful genetic resources to analyze disease processes.Many inbred strains have been bred for specific phenotypes. C57BL/6J mice are susceptible to high-fat diet-induced type II diabetes. 11 JF1 mice are especially sensitive to high-fat diet-induced diabetes and obesity, whereas MSM/Ms mice are resistant. 12 To date, however, there is little information about the difference in severity of pancreatitis among inbred strains of mice.Acute pancreatitis is an important disease that can be triggered by a variety of factors, including excessive alcohol consumption, 13-16 obstruction of the ampulla of Vater by gall stones, 17,18 and genetic factors. 19,20 Hereditary chronic pancreatitis is a rare form of early onset chronic pancreatitis, characterized by the onset of recurrent...

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Section: Discussionmentioning

confidence: 99%

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

Wang

Ohmuraya

Suyama

et al. 2010

Laboratory Investigation

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“…The most common R122H mutation eliminates this site of hydrolysis and, therefore, renders trypsin resistant to autolysis, resulting in higher concentrations of trypsin, autodigestion of the pancreas, and pancreatitis [1, 2, 3, 4, 9]. Both the R122H and the N29I substitution, the second most common cause of hereditary pancreatitis, have also been shown to significantly enhance autoactivation of human cationic trypsinogen in vitro which in turn leads to higher levels of trypsin being generated in pancreatic acinar cells [33].…”

Section: Discussionmentioning

confidence: 99%

“…Hereditary pancreatitis is a rare autosomal dominant disorder with about 80% penetrance and variable expressivity [for a review see 1, 2, 3, 4]. Onset of disease occurs at a mean age of 14.1 ± 11.9 years [5].…”

Section: Introductionmentioning

confidence: 99%

R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis

et al. 2001

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Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC→CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

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“…This has led to some confusion in the literature. We [22]andothers [23]have advocated the adoption of recently published recommendations for a nomenclature system for human gene mutations [24]. This states that for amino acid-based systems, the codon for the initiator methionine is codon 1.…”

Section: Methodsmentioning

confidence: 99%

Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

et al. 2001

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Background/Aims: Mutations in the cationic trypsinogen gene have been detected in patients with hereditary pancreatitis (HP). This study investigates the prevalence of the R122H, N29I, A16V and –28delTCC mutations in the common, non-hereditary forms of chronic pancreatitis and in a HP family. Methods: DNA was prepared from blood samples of 53 patients with chronic pancreatitis (36 alcoholic, 14 idiopathic and 3 hereditary), 20 alcoholic controls and 20 healthy, ethnically matched controls. The R122H and A16V mutations were identified by the polymerase chain reaction (PCR) and restriction enzyme digestion. A nested-PCR was used to identify the N29I mutation. The –28delTCC deletion and the C133807T polymorphism were sought by direct sequencing. Results: The R122H mutation was detected in 1 patient with alcoholic chronic pancreatitis and all 3 affected members of a HP family. The N29I, A16V and –28delTCC mutations were not detected in any of the study subjects. At the C133807T polymorphism, the C allele and C/C genotype were significantly increased in alcoholic chronic pancreatitis (p = 0.001 and p = 0.0004, respectively) while the T allele and CT genotype were significantly reduced (p = 0.001 and p = 0.004, respectively) compared to healthy controls. Conclusions: Mutations of the cationic trypsinogen gene are rarely found in chronic pancreatitis patients of typical aetiology. Screening for these mutations should be considered in those with a family history consistent with hereditary pancreatitis but may also be appropriate in a well-defined subgroup of patients with non-hereditary chronic pancreatitis, i.e. those who have developed the disease before the age of 30.

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Hereditary pancreatitis and mutations of the cationic trypsinogen gene

Cited by 14 publications

References 47 publications

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

Relationship of strain-dependent susceptibility to experimentally induced acute pancreatitis with regulation of Prss1 and Spink3 expression

R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis

Mutations of the Cationic Trypsinogen Gene in Hereditary and Non-Hereditary Pancreatitis

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