Human cationic trypsinogen (<i>PRSS1</i>) variants and chronic pancreatitis

Németh, Balázs Csaba; Sahin–Tóth, Miklós

doi:10.1152/ajpgi.00419.2013

Cited by 78 publications

(60 citation statements)

References 62 publications

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“…Such genes were selected among the genes annotated in the "Pancreatic Secretion Pathway" (map04972), available in the KEGG database (22). The 70 genes selected were classified into six groups according to the activity of the encoded protein or their role in the pathogenesis of pancreatitis: (i) genes encoding proteins potentially involved in premature intrapancreatic activation of trypsin (CFTR, PRSS1, PRSS2, SPINK1, CTRC, CTSB, KRT8 and CASR) (23)(24)(25)(26)(27)(28)(29)(30); (ii) CF modifier genes the risk increases for patients with residual pancreatic function (about 10% of cases). However, also excluding all such causes, about one-third of recurrent/ chronic pancreatitis remains idiopathic, and this number is higher in children, who seldom report the classical risk factors observed in adults (8).…”

Section: Miseq Panel Genesmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

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Genetic features of chronic pancreatitis (CP) have been investigated extensively, mainly by testing genes associated to the trypsinogen activation pathway. However, different molecular pathways involving other genes may be implicated in CP pathogenesis. A total of 80 patients with idiopathic chronic pancreatitis (ICP) were investigated using a Next-Generation Sequencing (NGS) approach with a panel of 70 genes related to six different pancreatic pathways: premature activation of trypsinogen, modifier genes of cystic fibrosis phenotype, pancreatic secretion and ion homeostasis, calcium signaling and zymogen granules (ZG) exocytosis, autophagy and autoimmune pancreatitis-related genes. We detected mutations in 34 out of 70 genes examined; of the 80 patients, 64 (80.0%) were positive for mutations in one or more genes and 16 (20.0%) had no mutations. Mutations in CFTR were detected in 32 of the 80 patients (40.0%) and 22 of them exhibited at least one mutation in genes of other pancreatic pathways. Of the remaining 48 patients, 13/80 (16.3%) had mutations in genes involved in premature activation of trypsinogen and 19/80 (23.8%) had mutations only in genes of the other pathways: 38 (59.3%) of the 64 patients positive for mutations showed variants in two or more genes. Our data, although to be extended with functional analysis of novel mutations, suggest a high rate of genetic heterogeneity in CP and that trans-heterozygosity may predispose to the ICP phenotype. online address: http://www.molmed.org

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Section: Miseq Panel Genesmentioning

confidence: 99%

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Sofia

Sacco

Surace

et al. 2016

Mol Med

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“…Mutations in the best characterized risk genes PRSS1 (cationic trypsinogen), SPINK1 (pancreatic secretory trypsin inhibitor), and CTRC (chymotrypsin C) stimulate activation of trypsinogen and result in elevated trypsin activity in the pancreas [4][5][6][7][8][9]. More recently, loss-of-function variants in the CPA1 gene encoding carboxypeptidase A1 were shown to increase risk for early onset CP [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

et al. 2017

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Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39-0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.

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“…Autoactivation plays an important role in ectopic activation of trypsinogen inside the pancreas, which can lead to pancreatitis. Hereditary pancreatitis is an autosomal dominant disorder caused by mutations in PRSS1 that result in increased intra-pancreatic trypsinogen activation (8,9). The mutations alter cleavage of regulatory nick sites by chymotrypsin C (CTRC) 2 and trypsin that control trypsinogen degradation and autoactivation (10).…”

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confidence: 99%

Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

Jancsó

Sahin–Tóth

2016

Journal of Biological Chemistry

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The human pancreas expresses two major trypsinogen isoforms, cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2). Mutations in PRSS1 cause hereditary pancreatitis by altering cleavage of regulatory nick sites by chymotrypsin C (CTRC) resulting in reduced trypsinogen degradation and increased autoactivation. Despite 90% identity with PRSS1 and a strong propensity for autoactivation, mutations in PRSS2 are not found in hereditary pancreatitis suggesting that activation of this isoform is more tightly regulated. Here, we demonstrated that CTRC promoted degradation and thereby markedly suppressed autoactivation of human anionic trypsinogen more effectively than previously observed with cationic trypsinogen. Increased sensitivity of anionic trypsinogen to CTRC-mediated degradation was due to an additional cleavage site at Leu-148 in the autolysis loop and the lack of the conserved Cys-139 -Cys-206 disulfide bond. Significant stabilization of anionic trypsinogen against degradation was achieved by simultaneous mutations of CTRC cleavage sites Leu-81 and Leu-148, autolytic cleavage site Arg-122, and restoration of the missing disulfide bridge. This stands in stark contrast to cationic trypsinogen where single mutations of either Leu-81 or Arg-122 resulted in almost complete resistance to CTRC-mediated degradation. Finally, processing of the trypsinogen activation peptide at Phe-18 by CTRC inhibited autoactivation of anionic trypsinogen, although cationic trypsinogen was strongly stimulated. Taken together, the observations indicate that human anionic trypsinogen is controlled by CTRC in a manner that individual natural mutations are unlikely to increase stability enough to promote intra-pancreatic activation. This unique biochemical property of anionic trypsinogen explains the lack of association of PRSS2 mutations with hereditary pancreatitis.

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Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis

Cited by 78 publications

References 62 publications

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Extensive Molecular Analysis Suggested the Strong Genetic Heterogeneity of Idiopathic Chronic Pancreatitis

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

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