PRSS1 – Hereditary Chronic Pancreatitis

Hereditary chronic pancreatitis is an autosomal dominant disorder characterized by recurrent pancreatic inflammation leading to chronic fibrosis and exocrine insufficiency. Segregation analysis in 112 European families comprising 418 affected individuals supports a dominant mode of inheritance with high penetrance and variable expressivity (PMID:15017610).

Germline variants in PRSS1 account for approximately 80% of familial cases. The canonical gain‐of‐function alleles p.Arg122His and p.Asn29Ile predominate, while additional missense mutations such as p.Arg122Cys (c.364C>T (p.Arg122Cys)), p.Arg116Cys, p.Ala16Val, p.Glu79Lys, and the novel p.Glu190Lys have been documented across diverse populations (PMID:11719509; PMID:11788572; PMID:30792736). Gene conversion events further illustrate mutational heterogeneity.

Functional assays demonstrate that classic PRSS1 mutations disrupt regulatory autolysis and chymotrypsin C–mediated degradation, resulting in enhanced trypsinogen autoactivation and elevated intrapancreatic trypsin levels (PMID:22539344). Misfolding variants like p.Glu190Lys stimulate autoactivation without secretion defects, whereas other rare alleles induce endoplasmic reticulum stress, indicating multiple pathogenic mechanisms (PMID:30792736).

In vivo, transgenic mice expressing human PRSS1^R122H develop acute and chronic pancreatitis with histopathological features mirroring human disease, underscoring the causal role of increased trypsin activity (PMID:31550238). The natural history in a national French cohort further confirms early onset, high penetrance (93%), and progression to exocrine/endocrine insufficiency and pancreatic cancer (PMID:18755888).

Conflicting evidence arises for variants such as p.Ala121Thr, which functional studies classify as functionally benign and non‐segregating, cautioning against overinterpretation of unvalidated alleles (PMID:20452997).

Collectively, these data meet ClinGen criteria for a Definitive gene–disease relationship. Robust genetic segregation, recurrent pathogenic variants, and concordant functional and animal model evidence support the clinical utility of PRSS1 testing for early diagnosis, family counseling, and risk stratification in hereditary chronic pancreatitis.

Key Take‐home: PRSS1 mutations drive autosomal dominant hereditary chronic pancreatitis through mechanisms of enhanced trypsin activation and misfolding, justifying routine genetic screening for timely intervention.

References

• Clinical gastroenterology and hepatology • 2004 • Clinical and genetic characteristics of hereditary pancreatitis in Europe PMID:15017610
• The Journal of biological chemistry • 2002 • Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 → Cys) that alters autoactivation and autodegradation of cationic trypsinogen. PMID:11719509
• Gut • 2002 • Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis. PMID:11788572
• The Journal of biological chemistry • 2012 • Increased activation of hereditary pancreatitis-associated human cationic trypsinogen mutants in presence of chymotrypsin C. PMID:22539344
• Journal of medical genetics • 2010 • Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations. PMID:20452997
• Frontiers in genetics • 2019 • Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis. PMID:30792736
• The Journal of clinical investigation • 2020 • Trypsin activity governs increased susceptibility to pancreatitis in mice expressing human PRSS1R122H. PMID:31550238
• Gut • 2009 • The natural history of hereditary pancreatitis: a national series. PMID:18755888
• The American journal of medicine • 2001 • Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. PMID:11755505

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