Disease relevance of PRSS1

• Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease [1].
• RESULTS: In six of the 10 patients that fulfilled the criteria for hereditary pancreatitis, but in none of the control subjects, mutations in the PRSS1 gene were found [2].
• METHODS: After exclusion of patients with trypsinogen (PRSS1) mutations, cystic fibrosis, or pulmonary disease, and with known risk factors for pancreatitis 67 patients with idiopathic chronic pancreatitis (ICP) from northwest Germany and 60 geographically and ethnically matched controls were recruited [3].
• Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance [4].
• All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma [4].

Psychiatry related information on PRSS1

• The strongest relationship found in this study was between the CSQ and PRSS catastrophising scales and depressive symptoms [5].
• Interestingly, the few (nine) subjects who had both early onset alcoholism and antisocial personality disorder had a higher plasma tryptophan but similar TRYP/LNAA ratio to the others [6].

High impact information on PRSS1

• Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis [1].
• Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor [7].
• Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene [8].
• We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype [8].
• The gene for this disease has recently been mapped to chromosome 7q35, and the defect is believed to be caused by a mutation in the cationic trypsinogen gene [9].

Chemical compound and disease context of PRSS1

• Chronic pancreatitis in childhood is frequently associated with mutations of the cationic trypsinogen gene (serine protease 1; PRSS1) [10].
• Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 --> Cys) that alters autoactivation and autodegradation of cationic trypsinogen [11].
• The gene, or at least one of the genes, responsible for hereditary pancreatitis has been mapped to the long arm of chromosome 7 and a missense mutation, an arginine to histidine substitution at residue 117 in the trypsinogen cationic gene (try4) has been shown to segregate with the HP phenotype [12].
• Bacterial mutagenic evaluation of Luxabendazole, a new broad spectrum anthelmintic, with the Salmonella typhimurium His- and the Escherichia coli Tryp- reversion tests [13].

Biological context of PRSS1

• Because of the incomplete pickup of PRSS1 mutations, particularly of a limited mutation panel of R122H and N291 (perhaps with A16V), a diagnosis of HP cannot be ruled out by molecular genetic testing alone [14].
• Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in hereditary pancreatitis [4].
• No mutation was found in the PRSS1 gene among our patients suggesting further genetic heterogeneity for hereditary and idiopathic chronic pancreatitis [15].
• Interaction between trypsinogen isoforms in genetically determined pancreatitis: mutation E79K in cationic trypsin (PRSS1) causes increased transactivation of anionic trypsinogen (PRSS2) [16].
• In three patients, the novel point mutations L104P, R116C, and C139F of the cationic trypsinogen were found [17].

Anatomical context of PRSS1

• METHODS: Two subjects from HP families (including a 93 year old subject with PRSS1 R122H without pancreatitis), one with chronic pancreatitis and one with a normal pancreas, were studied [18].
• MAIN OUTCOME MEASURES: In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded [19].
• Homo sapiens possess several trypsinogen or trypsinogen-like genes of which three (PRSS1, PRSS2, and PRSS3) produce functional trypsins in the digestive tract [20].
• PCR amplificates from leukocyte or buccal swab DNA showed no mutation of exon 3 of cationic trypsinogen [21].
• TRY2 mRNA was detected in all 6 colorectal tumor cell lines, whereas TRY1 mRNA was expressed only in the metastatic tumor lines, showing that the high levels of TRY expression in the metastatic tumor lines are likely due to up-regulation of TRY1 [22].

Associations of PRSS1 with chemical compounds

• RESULTS: A cytosine (C) to thymine (T) mutation at position 2441 (g.2441C>T) of the PRSS1 gene, which results in a substitution of arginine by cysteine at position 116 (R116C) of CT, was identified by direct sequencing in both clinically affected members of the family but was not found in the unaffected member [23].
• The recombination replaced at least 289 nucleotides with the paralogous sequence from the anionic trypsinogen gene (serine protease 2; PRSS2), and resulted in the PRSS1 mutations c.86A > T and c.161A > G, causing the amino acid substitutions N29I and N54S, respectively [10].
• Mutational screening identified a single A to T mutation resulting in an asparagine to isoleucine transition mutation at position 21 (N21I) in cationic trypsinogen [24].
• Third, evolutionary divergence from threonine to asparagine at residue 29 in human cationic trypsinogen provides additional advantage [25].
• However, trypsin-I presented one lysine at position 11, being the first report of this amino acid in the sequence of a lepidopteran digestive trypsin [26].

Regulatory relationships of PRSS1

• METHODS: The coding region of the exon 2 and 3 of the CT gene of 523 patients with chronic nonalcoholic pancreatitis (108 patients with suspected hereditary pancreatitis (HP) and 415 patients with "idio pathic" pancreatitis [IP]) and 82 controls was analyzed after polymerase chain reaction amplification [17].
• Serum immunoreactive cationic trypsinogen levels were determined in 99 control subjects and 381 cystic fibrosis (CF) patients [27].
• The Try2 gene was always expressed at much lower levels than Try1 or Chy1 [28].
• Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen [29].

Other interactions of PRSS1

• We performed mutational analysis for two PRSS1 mutations (R122H, N29I) and four specific SPINK1 gene mutations (M1T, L14P, N34S, P55S) and compared the results with a control group of 120 healthy Dutch subjects [2].
• No difference was observed in the frequency of PRSS1 or PSTI polymorphisms in neonates carrying or not carrying CF mutations [30].
• In human, the three genes are syntenic on HSA7, but they are not on a conserved segment: CASP2 and PRSS1 are localized to 7q35, while NPY is localized to 7p15 [31].
• METHODS: 124 patients with non-alcoholic chronic pancreatitis (with PRSS1 or SPINK1 mutations or idiopathic pancreatitis) and 64 healthy controls were investigated for the AAT mutations PiS and PiZ, and the PiM determining variants R101H, V213A, E376D [32].
• Identification of a novel pancreatitis-associated missense mutation, R116C, in the human cationic trypsinogen gene (PRSS1) [33].

Analytical, diagnostic and therapeutic context of PRSS1

• RESULTS: PRSS1 wild-type (R122) and mutant (H122) allele expression was equivalent in multiple (> 3) samples from the phenotypically affected and non-penetrant subjects with R122H genotypes using allele specific quantitative reverse transcription-polymerase chain reaction (RT-PCR) and intron spanning nested RT-PCR followed by cDNA sequencing [18].
• A case-control-study of 38 pairs of patients with either PRSS1 or SPINK1 mutations showed that the probability of duct dilatation, diabetes and calcification was slightly higher in patients having a SPINK1 mutation [19].
• MATERIALS AND METHODS: DNA samples containing either the known c.365G>A or c.365 through 366GC>AT variant in exon 3 of PRSS1 were used as positive controls to establish a denaturing high performance liquid chromatography (DHPLC) assay [34].
• A simple method for the purification of anionic and cationic trypsinogen and trypsin from human pancreatic juice applying affinity chromatography on aprotinin coupled Sepharose is described together with the N-terminal amino acid sequences for both trypsinogens [35].
• Using whole mount in situ hybridization, gene expression of Try1, Try2 and Chy1 has been localized not only in the distensible anterior region of the midgut of lice but sometimes also in the area following the distensible region [28].

References