“Mutations in the PRSS1 gene are strongly associated with hereditary pancreatitis and lead to increased intrapancreatic trypsin activity.”

Increased trypsin activity was the cause of more severe pancreatitis in PRSS1R122H mice. In vitro biochemical studies have shown that gain-of-function PRSS1 mutations increase trypsinogen auto-activation and/or inhibit trypsinogen degradation. Collectively, these results strongly support the idea that the R122H mutation of PRSS1 causes severe pancreatitis through increased trypsin activity.

The diagnosis of PRSS1-related HP is established in a proband with episodes of AP, RAP, and/or CP and a heterozygous pathogenic gain-of-function variant in PRSS1 identified by molecular genetic testing. High-penetrance PRSS1 pathogenic variants include p.Asn29Ile and p.Arg122His, and lower-penetrance pathogenic variants include p.Arg16Val, Asp22Gly, p.Lys23Arg, p.Asn29Thr, and p.Arg122Cys.

These replicated studies revealed PRSS1 is definitively associated with autosomal dominant inheritance pancreatitis. Most pathogenic variants significantly enhance autoactivation in vitro, whereas some mutations such as p.R122H additionally inhibit autolysis of the active enzyme.

Mutations in PRSS1 cause hereditary pancreatitis by reducing chymotrypsin C (CTRC)-dependent degradation of cationic trypsinogen and thereby promoting trypsinogen autoactivation. Rates of N-terminal processing by CTRC were increased 3.3-fold by mutation p.A16V and 1.7-fold by mutation p.P17T, relative to wild type. As a consequence of stronger N-terminal processing, mutants p.A16V and p.P17T exhibited increased initial rates of autoactivation and developed higher trypsin levels.

Hereditary pancreatitis is caused by mutations in human cationic trypsinogen (PRSS1) which lead to increased autoactivation by altering chymotrypsin C (CTRC)-dependent trypsinogen activation and degradation. Recent studies uncovered that PRSS1 mutations alter the regulation of activation and degradation of cationic trypsinogen by chymotrypsin C (CTRC). Only one of the 12 variants tested, p.D100H exhibited increased activation in the presence of CTRC.

Some PRSS1 gene mutations result in the production of a cationic trypsinogen enzyme that is prematurely converted to trypsin while it is still in the pancreas. Other mutations prevent trypsin from being broken down. The most common PRSS1 gene mutation that causes hereditary pancreatitis replaces the amino acid arginine with the amino acid histidine at position 122 in the enzyme (written Arg122His or R122H). As a result of this mutation, the enzyme is not able to be broken down, even when it is no longer bound to calcium. Trypsin activity in the pancreas can damage pancreatic tissue.

Mutations in the PRSS1 gene cause most cases of hereditary pancreatitis. Some PRSS1 gene mutations that cause hereditary pancreatitis result in the production of a cationic trypsinogen enzyme that is prematurely converted to trypsin while it is still in the pancreas. Other mutations prevent trypsin from being broken down. These changes result in elevated levels of trypsin in the pancreas. Trypsin activity in the pancreas can damage pancreatic tissue and can also trigger an immune response, causing inflammation in the pancreas.

PRSS1 gene mutations have been directly implicated in the pathophysiology of hereditary and idiopathic chronic pancreatitis by producing an autolysis-resistant trypsin and/or facilitating auto-activation. The results suggest that mutations in the PRSS1 gene are sufficient to induce pancreatic disease.

Several biochemical studies demonstrated that most of these mutations led to enhanced trypsinogen auto-activation and/or increased trypsin stability. Then the pancreatic protease anti-protease equilibrium may be disturbed. And this imbalance may initiate the subsequent auto-digestion and pancreatitis.

HP is generally caused by gain-of-function mutations in the cationic trypsinogen gene (PRSS1). Two gain-of-function mutations, R122H and N29I, have been identified in the vast majority of hereditary pancreatitis kindreds in the United States and Europe, comprising 90% of PRSS1-positive HP cases. Additional copies of PRSS1 act as gain-of-function mutations by increasing trypsin expression.

The mutations exert their pathogenic effect either by increasing intra-pancreatic trypsinogen activation (trypsin pathway). While the common biochemical phenotype is increased autoactivation of trypsinogen, this effect may be achieved in a number of different ways. The clinically most frequent mutation p.Arg122His blocks chymotrypsin C (CTRC)-dependent degradation of cationic trypsinogen and thereby increases autoactivation and accumulation of trypsin.

Mutations in human cationic trypsinogen (PRSS1) cause autosomal dominant hereditary pancreatitis. We found that in the presence of CTRC, trypsinogen mutants associated with classic hereditary pancreatitis (N29I, N29T, V39A, R122C, and R122H) autoactivated at increased rates and reached markedly higher active trypsin levels compared with wild-type cationic trypsinogen.

Genetic testing identified pathogenic compound mutations in SPINK1 (c.194+2T>C) and PRSS1 (c.623G>C), confirming a diagnosis of hereditary pancreatitis. Family screening showed variable inheritance of PRSS1 mutations, with all family members carrying both variants showing pancreatic calcifications except one.

More than 40 mutations in the PRSS1 gene have been found to cause hereditary pancreatitis, a condition characterized by recurrent episodes of inflammation of the pancreas (pancreatitis), which can lead to a loss of pancreatic function. Some PRSS1 gene mutations result in the production of a cationic trypsinogen enzyme that is prematurely converted to trypsin while it is still in the pancreas. Other mutations prevent trypsin from being broken down. These changes result in elevated levels of trypsin in the pancreas. Trypsin activity in the pancreas can damage pancreatic tissue and can also trigger an immune response, causing inflammation in the pancreas and leading to episodes of pancreatitis.

Mutations in PRSS1 typically result in a trypsin protein that is either prematurely activated or resistant to degradation, causing autosomal dominant pancreatitis in 60% to 100% of families with hereditary pancreatitis. PRSS1 encodes trypsin-1 (cationic trypsinogen), a major pancreatic digestive enzyme.

The biochemical studies of the pancreatitis-associated p. R122H mutations of human cationic trypsinogen in vitro show that this trypsinogen variant has an increased propensity for auto-activation and is resistant to degradation by chymotrypsin C. However, this mutation has pleiotropic effects rather than being exclusively an activating mutation, and there is no direct evidence for increased intracellular trypsin activity in patients with hereditary pancreatitis due to this mutation.

Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c. 365G>A (p. R122H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo.

PRSS1 mutations are the primary genetic cause of hereditary pancreatitis, with gain-of-function effects leading to elevated trypsin activity within the pancreas via mechanisms like increased autoactivation or resistance to degradation, as established in major reviews by NIH and peer-reviewed literature up to 2025.