Trypsinogen Copy Number Mutations in Patients With Idiopathic Chronic Pancreatitis

Masson, Emmanuelle; Maréchal, Cédric Le; Chandak, Giriraj Ratan; Lamoril, J.; Bézieau, Stéphane; Mahurkar, Swapna; Bhaskar, Suryanarayanan; Reddy, D. Nageshwar; Chen, Jian‐Min; Férec, Claude

doi:10.1016/j.cgh.2007.10.004

Cited by 75 publications

(75 citation statements)

References 48 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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“…In conclusion, all the established mutations in the cationic trypsinogen gene, including the copy number polymorphism, are not a common cause of tropical calcific pancreatitis in the Indian population [37,66] . The model for etiopathogenesis of TCP emerging from the available information is presented in Figure 1.…”

Section: Resultsmentioning

confidence: 83%

“…triplication of a 605 kilobase segment containing the PRSS1 and PRSS2 genes have been reported in hereditary pancreatitis patients [65] . A study by Masson et al [66] revealed the molecular basis of 6% of young ICP patients demonstrating chronic pancreatitis to be a genomic disorder. However, no copy number variations were found in TCP patients to provide evidence, showing that trypsinogen gene mutations do not play an important role in the pathogenesis of TCP in the Indian population.…”

Section: P R E V I O U S S T U D I E S W I T H S Y N T H E T I C S U mentioning

confidence: 99%

Genetic mechanisms underlying the pathogenesis of tropical calcific pancreatitis

Mahurkar¹,

Reddy²,

Rao³

et al. 2009

WJG

Self Cite

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Chronic pancreatitis is known to be a heterogeneous disease with varied etiologies. Tropical calcific pancreatitis ( TCP) is a severe form of chronic pancreatitis unique to developing countries. With growing evidence of genetic factors contributing to the pathogenesis of TCP, this review is aimed at compiling the available information in this field. We also propose a two hit model to explain the sequence of events in the pathogenesis of TCP.

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“…In the case of the PRSS1 gene, pancreatitis can be caused by various molecular mechanisms. These include the increase of stability by mutation in the autolysis site [5,8,73], increase of autocatalytic conversion of trypsinogen to active trypsin by mutation modifying the "substrate" property of trypsinogen [12,65], disturbance of intracellular transport resulting in colocalization of trypsinogen with lysosomal enzyme, cathepsin B [9,74], or triplication [31] and duplication [39] of the copy number of trypsinogen gene.…”

Section: Spink1/spink3 As a Trypsin Inhibitormentioning

confidence: 99%

The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

Ohmuraya

Yamamura

2011

Exp. Anim.

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Serine protease inhibitor Kazal type 1 (SPINK1) was originally identified as a trypsin inhibitor by Kazal et al. in 1948. SPINK1 is strongly elevated in pancreatitis and the elevation correlates with the severity of disease. In 2000, mutations in the SPINK1 gene were shown to be associated with chronic pancreatitis. Since then, there have been many reports on association between mutations in the SPINK1 genes and patients with pancreatitis. In 1982, SPINK1 was shown to be identical to tumor associated trypsin inhibitor (TATI). In addition, sequence similarities were detected between human epidermal growth factor (EGF) and human SPINK1 in 1983. Actually, SPINK1 was shown to stimulate growth of several cell lines including cancer cells in 1985. Recent clinical studies showed that high levels of SPINK1 protein in serum or urine were associated with adverse outcome in various cancer types. However, there was little evidence that showed in vivo function of SPINK1. Surprisingly, mice deficient in Spink3 (a mouse homologue gene of human SPINK1) showed excessive autophagy, but not pancreatitis in the exocrine pancreas, leading to autophagic cell death. We also demonstrated that SPINK1 acts as a growth factor through EGFR signaling. These data indicate that the role of the SPINK1 is not just as a trypsin inhibitor, but also as a growth factor as well as a negative regulator of autophagy. In this review, we summarize the roles of SPINK1/Spink3 in pancreatic diseases based on the data obtained from analyses using mouse models.

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Trypsinogen Copy Number Mutations in Patients With Idiopathic Chronic Pancreatitis

Cited by 75 publications

References 48 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 mechanisms underlying the pathogenesis of tropical calcific pancreatitis

The Roles of Serine Protease Inhibitor Kazal Type 1 (SPINK1) in Pancreatic Diseases

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