Genetic risk in chronic pancreatitis: the misfolding-dependent pathway

Sahin–Tóth, Miklós

doi:10.1097/mog.0000000000000380

Cited by 81 publications

(18 citation statements)

References 58 publications

(59 reference statements)

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“…Mutations in digestive enzymes can alter their folding and result in reduced secretion with intracellular retention, degradation and resultant endoplasmic reticulum (ER) stress. This mechanism has been observed with a subset of PRSS1 variants and in pathogenic CPA1 variants [33]. Only four of 23 PNLIP variants showed reduced secretion consistent with the possibility of protein misfolding.…”

Section: Discussionsupporting

confidence: 59%

Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

et al. 2019

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Objectives. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. Methods. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. Results. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P<0.0001). Conclusions. Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of chronic pancreatitis.

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Section: Discussionsupporting

confidence: 59%

Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

et al. 2019

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“…Endoplasmic reticulum (ER) stress induced by protein misfolding and overaccumulation in the ER lumen has been documented to be chronically activated in CP and may thus be an important pathogenic mechanism in this disease 11,12 . During ER stress, also known as the unfolded protein response, ER sensors such as ATF6, PERK, and IRE1 become activated and promote the degradation of misfolded proteins, production of molecular chaperones, and cell apoptosis 13,14 .…”

Section: Introductionmentioning

confidence: 99%

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

et al. 2019

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Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.

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“…In combination with other stressors, the presence of PNLIPRP2 aggregates could activate cell death and inflammatory pathways leading to pancreatitis. A similar mechanism was reported for misfolding PRSS1 and carboxypeptidase A1 (CPA1) mutants, which appear to cause pancreatitis through endoplasmic reticulum stress [ 22 ]. Herein, we investigated whether the p.W358X PNLIPRP2 allele is a genetic risk factor for CP in patients with alcohol-related and non-alcohol-related CP.…”

Section: Introductionmentioning

confidence: 62%

The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis

et al. 2018

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A nonsense variant (p.W358X) of human pancreatic lipase related protein 2 (PNLIPRP2) is present in different ethnic populations with a high allele frequency. In cell culture experiments, the truncated protein mainly accumulates inside the cells and causes endoplasmic reticulum stress. Here, we tested the hypothesis that variant p.W358X might increase risk for chronic pancreatitis through acinar cell stress. We sequenced exon 11 of PNLIPRP2 in a cohort of 256 subjects with chronic pancreatitis (152 alcoholic and 104 non-alcoholic) and 200 controls of Hungarian origin. We observed no significant difference in the distribution of the truncation variant between patients and controls. We analyzed mRNA expression in human pancreatic cDNA samples and found the variant allele markedly reduced. We conclude that the p.W358X truncation variant of PNLIPRP2 is expressed poorly and has no significant effect on the risk of chronic pancreatitis.

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Genetic risk in chronic pancreatitis: the misfolding-dependent pathway

Cited by 81 publications

References 58 publications

Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis

The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis

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