Three Cases of Hereditary Pancreatitis in Two Households in the Same Family Associated with R122H Mutation in Cationic Trypsinogen Gene / 대한소화기학회지

Hereditary pancreatitis is a rare, autosomal dominant, inherited disease characterized by recurrent attacks of acute pancreatitis with the development of chronic pancreatitis and an increased risk of pancreatic cancer. R122H or N29I mutation in cationic trypsinogen (protease serine 1, PRSS1) gene causes hereditary pancreatitis. R122H mutation is the most common mutation that causes pancreatitis by preventing deactivation of trypsin within the pancreas and prolonging its action. Three members of the family, the patient, her elder son, and her niece experienced recurrent attacks of pancreatitis. We analyzed five exons of the PRSS1 gene in DNA samples of five family members including her husband and younger son who were asymptomatic. We found out that four members of the family, the patient, her two sons, and her niece, had R122H mutation in the exon 3 of PRSS1 gene. Finally, we diagnosed hereditary pancreatitis in two households in the same family.

A Case of R122H Mutation of Cationic Trypsinogen Gene in a Pediatric Patient with Hereditary Pancreatitis Complicated by Pseudocyst and Hemosuccus Pancreaticus / 대한소화기학회지

Hereditary pancreatitis is a rare autosomal dominant inherited disease with 80% penetration rate. The disease is characterized by recurrent episodes of pancreatitis often beginning in childhood, positive family history with at least two other affected members and no known precipitating factors. Most forms of hereditary pancreatitis are caused by one of two commoner mutations, R122H in exon 3 and N29I in exon 2 of the cationic trypsinogen (CT) (PRSS1) gene, located on chromosome 7. These genetic defects are speculated to cause excessive trypsin activity or to prevent inactivation of prematurely activated trypsin, resulting in pancreatitis. We performed mutation analysis of a Korean family with two members having clinically suspicious hereditary pancreatitis. We analyzed the CT gene in DNA samples extracted from peripheral blood of five family members. First of all, polymerase chain reaction and restriction enzyme digestion were performed in exon 3 of the CT gene. And then DNA products were purified and sequenced. We found out that three members of the family, the mother and two daughters, had a R122H mutation of the CT gene. We report the first family of hereditary pancreatitis associated with the CT gene mutation, an arginine to histidine amino acid substitution at residue 122, in Korea.

Hereditary Pancreatitis / 대한소화기학회지

Hereditary pancreatitis (HP) is an autosomal dominant inherited disease characterized by recurrent episodes of pancreatitis often beginning in childhood, a family history of at least 2 other affected members, and the absence of known etiologic factors. The discovery of mutations in cationic trypsinogen gene (PRSS1) in HP not only provided insights into the molecular mechanisms of pancreatitis, but also opened a new era in the field of chronic pancreatitis. The detection of mutations in serine protease inhibitor, Kazal type 1 (SPINK1) and CFTR in patients with hereditary or idiopathic chronic pancreatitis has placed the emphasis on the importance of genetic mutations in pancreatitis. Because the estimated cumulative risk of pancreatic cancer developement in hereditary pancreatitis is nearly 40%, screening tests are important in selected cases. There are no specific medical therapies recommended in patients with HP. Registration of patients with Nationwise Registries is essential if management strategies are to be improved and genetic research to be continued.

Hereditary Pancreatitis / 대한소화기학회지

The first family of hereditary pancreatitis was described in 1952. The mode of inheritance is autosomal dominant trait with an 80% of penetrance rate. Although hereditary pancreatitis is rare, this disorder has provided valuable insights in understanding the pathophysiology of pancreatitis and pancreatic cancer. The causative gene of hereditary pancreatitis was identified in 1996 through mutational analysis of genes within chromosome 7q35. Most forms of hereditary pancreatitis are caused by one of two common mutations, R122H in the third exon or N29I in the second exon of the cationic trypsinogen gene (protease serine 1, PRSS1). R122H mutation is the most common PRSS1 mutation. Additional mutations of the cationic trypsinogen gene have been described. In Korea, first family of hereditary pancreatitis with cationic trypsinogen gene mutation revealed an arginine to histidine amino acid substitution at the residue 122. Patients with hereditary pancreatitis present with symptoms at an early age and have significant risk for the development of chronic pancreatitis and pancreatic cancer. The risk of pancreatic cancer is estimated to be 53-fold higher after the age of 50 years than the general population. The risk of pancreatic cancer is not related to the type of mutation. Since hereditary pancreatitis is a strong risk factor for pancreatic cancer, it is important to establish a diagnostic criteria for diagnosis and surveillance. However, there are potential benefits, risks and limitations in genetic testing for hereditary pancreatitis. It is difficult to provide the proper treatment, but recent developments in therapeutic approaches may be helpful in caring hereditary pancreatitis. This article includes the current status, pathogenesis, clinical features, and management of hereditary pancreatitis including the aspects of pancreatic cancer.

Mutations of SPINK1 and PRSS1 Gene in Korean Patients with Chronic Pancreatitis / 대한소화기학회지

BACKGROUND/AIMS: It has been found that mutations of cationic trypsinogen gene (PRSS1) and serine protease inhibitor, Kazal type 1 gene (SPINK1) increase the susceptibility of chronic pancreatitis (CP). Specifically, mutations in the PRSS1 gene are related to the occurrences of hereditary and idiopathic pancreatitis while SPINK1 mutations are known to act as a disease modifier and are associated with idiopathic CP. However, the association of SPINK1 mutations with alcoholic CP is still controversial. We investigated the prevalence of PRSS1 and SPINK1 mutations in idiopathic and alcoholic CP in Korea. METHODS: Seventy-one Korean patients with CP (alcoholic: 47, idiopathic: 22 and familial: 2) and 19 controls were included in this studies. Genomic DNA was extracted from peripheral blood of the patients. Mutations of SPINK1 (exon 3: N34S) and PRSS1 (exon 2: N29I, exon 3: R122H) genes were detected by PCR-RFLP methods. For the detection of SPINK1 mutation, restriction endonuclease PstI and BsrDI were used, while Sau3A and AflIII were used for the defection of PRSS1 mutation. RESUTLS: Only one patient (2.1%) with alcoholic CP was a heterozygote for SPINK1 (N34S) mutation. Mutation in the PRSS1 (N29I, R122H) gene was not found in any group of CP patients. Additionally, we could not find any mutations of SPINK1 or PRSS1 in the control group. CONCLUSIONS: SPINK1 and PRSS1 mutations are not related to the development of CP in Korea.

Cationic Trypsinogen Gene Mutation in Patients with Chronic Idiopathic Pancreatitis / 대한소화기학회지

BACKGROUND/AIMS: Mutation of Cationic trypsinogen gene is clearly associated with hereditary pancreatitis and plays an important role in the pathogenesis of pancreatitis. According to literature, this mutation is occasionally occurred in patients with pancreatitis in Western countries and Japan. The aim of this study was to find out whether the mutation was observed in Korean patients with chronic idiopathic pancreatitis. METHODS: Peripheral blood samples of 11 patients with chronic idiopathic pancreatitis were collected consecutively, and DNA was extracted from the samples. Polymerase chain reaction was performed in exon 2 and 3 of cationic trypsinogen gene. Then, DNA products were purified and sequenced. RESULTS: The mutation was not found in exon 2 and 3 of cationic trypsinogen gene in these patients. CONCLUSIONS: There was no cationic trypsinogen mutation in Korean patients with chronic idiopathic pancreatitis. Further large sampled cohort study is needed.

Classification of chronic pancreatitis including the genetics of trypsin SPINK1 and CFTR

Chronic pancreatitis is not one disease; it is a pathway of injury and fibrosis driven by many factors. The role of genetics is emerging as a major factor, both in terms of understand pathogenesis, and in terms of identifying risk factors and mechanisms. Use of the TIGAR-O classification system, or others will be useful research tools to determine gene-gene, gene-environment, and other interactions that contribute to development of an otherwise mysterious disease