A novel p.Ser282Pro<i>CPA1</i>variant is associated with autosomal dominant hereditary pancreatitis

Kujko, Aleksandra; Berki, Dorottya M.; Oracz, Grzegorz; Wejnarska, Karolina; Antoniuk, Justyna; Wertheim–Tysarowska, Katarzyna; Kołodziejczyk, Elwira; Bal, Jerzy; Sahin–Tóth, Miklós; Rygiel, Agnieszka Magdalena

doi:10.1136/gutjnl-2017-313816

Cited by 29 publications

(15 citation statements)

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“…The discovery that PRSS1 overactivation is associated with CP development has been regarded as an essential step forward in understanding the molecular mechanisms of CP pathogenesis in past decades 5 . Additionally, the ER stress response caused by digestive enzymes is considered a critical disease risk factor for CP progression 12,15,21,22 . Previous studies have shown that PRSS1 protein misfolding contributes to the development and progression of CP through inducing ER stress responses 15 , suggesting a protein misfolding-dependent pathway for CP onset and progression 12 .…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…Indeed, expression of the CPA1 p.Asn256Lys variant, which was found in 7 NACP patients but not in controls, resulted in ER stress in AR42J rat acinar cells . More recently, a novel CPA1 variant, p.Ser282Pro, found in two Polish families with hereditary pancreatitis, has been shown to induce ER stress to a comparable degree as the p.Asn256Lys variant (Kujko et al, 2017).…”

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No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort

Zhou

Berki

et al. 2017

Human Mutation

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Rare functionally defective carboxypeptidase A1 (CPA1) variants have been reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, independent replication has so far been lacking, particularly in Asian cohorts where initial studies employed small sample sizes. Herein we performed targeted next-generation sequencing of the CPA1 gene in 1112 Han Chinese idiopathic chronic pancreatitis (ICP) patients – the largest ICP cohort so far analyzed in a single population – and 1580 controls. Sanger sequencing was used to validate called variants, and the CPA1 activity and secretion of all newly found variants were measured. A total of 18 rare CPA1 variants were characterized, 11 of which have not been previously described. However, no significant association was noted with ICP irrespective of whether all rare variants [20/1112 (1.8%) in patients vs. 24/1580 (1.52%) in controls; P=0.57] or functionally impaired variants [3/1112 (0.27%) in patients vs. 2/1580 (0.13%) in controls; P=0.68] were considered.

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“…Nevertheless, it has not been analyzed if CPA1 variants are causative risk factors for the familial or hereditary disease. However, a study by Kujko et al shed light on this issue, showing that the novel CPA1 variant p.Ser282Pro co-segregated with pancreatitis in two Polish families with autosomal dominant hereditary pancreatitis [56]. The age of onset for index patients in these two families was 17 and 12 years.…”

Section: Cpa1mentioning

confidence: 99%

Genetic Risk Factors in Early-Onset Nonalcoholic Chronic Pancreatitis: An Update

Wertheim–Tysarowska¹,

Oracz

Rygiel³

2021

Genes

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Chronic pancreatitis (CP) is a progressive, irreversible inflammatory disorder of the pancreas, which results from interrelations between different genetic and environmental factors. Genetic variants are the primary cause of the disease in early-onset nonalcoholic CP patients. Novel CP-associated genes are continuously emerging from genetic studies on CP cohorts, providing important clues for distinct mechanisms involved in CP development. On the basis of functional studies, the genetic alterations have been sub-grouped into CP-driving pathological pathways. This review focuses on the concept of CP as a complex disease driven by multiple genetic factors. We will discuss only well-defined genetic risk factors and distinct functional pathways involved in CP development, especially in the context of the early-onset nonalcoholic CP group. The diagnostic implications of the genetic testing will be addressed as well.

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A novel p.Ser282ProCPA1variant is associated with autosomal dominant hereditary pancreatitis

Cited by 29 publications

References 2 publications

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

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

No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort

Genetic Risk Factors in Early-Onset Nonalcoholic Chronic Pancreatitis: An Update

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