Study for the molecular pathogenesis of the idiopathic chronic pancreatitis, especially familial pancreatitis

我们研究了影响家族性慢性胰腺炎（CP）的遗传异常，以了解其发病机制。我们回顾了日本和世界上家族性胰腺炎的报道。遗传性胰腺炎的诊断依据Gross的标准，即该家族两代中有两个以上的胰腺炎患者，且发病时间在10岁之前。然而，由于家庭规模的减少，在日本很难采用格罗斯的标准。本研究对胰腺分泌胰蛋白酶抑制剂（PSTI）基因、Reg i - α基因和Reg i - β基因进行southern blot分析，未发现家族性CP的遗传异常。近年来，在美国和意大利家族中报道了阳离子胰蛋白酶原基因R117H和N21I突变（Whitcomb， 1996和1997）。R117H突变导致急性炎症时活性胰蛋白酶消失。我们提取了24名儿童期表现出胰腺炎症状的门诊患者和17个家庭的4名健康亲属的基因组DNA。在4个家族的7例急性胰腺炎患者中发现了3外显子R117H突变。所有患者均在28岁前出现上述症状，并伴有胰腺钙化。但外显子2的N21I突变未在任何家族中检测到。我们没有发现胰蛋白酶原基因的其他变化。通过胰蛋白酶原基因突变诊断遗传性胰腺炎的病例，不论发病年龄和家族成员数，仅1例。本研究表明，胰蛋白酶原基因外显子3突变是日本遗传性胰腺炎的一个常见的重要因素，与白种人一样。总之，胰蛋白酶在胰腺炎的发病机制中起重要作用。

We studied genetic abnormalities affecting familial chronic pancreatitis (CP) in order to understandg its pathogenesis. We reviewed the reports of familial pancreatitis in Japan and the world. Hereditary pancreatitis was diagnosed according to Gross's criteria, that is, the family included more than two pancreatitis patients in two generations and their onset was before the age of ten. However, it was difficult to employ Gross's criteria in Japan because of the decrease in the size of families.We did not find the genetic abnormalities in familial CP using southern blot analysis of pancreatic secretary trypsin inhibitor (PSTI) gene, Reg I-alpha gene and Reg I-beta gene. Recently, two mutations, R117H and N21I,in cationic trypsinogen gene were reported in American and Italian families (Whitcomb, 1996 and 1997). The R117H mutation induces the disappearance of active trypsin at acute inflammation.We extracted genomic DNA from twenty-four outpatients in our clinic who showed symptoms of pancreatitis in childhood and four healthy relatives in 17 families. The R117H mutation in exon 3 was found in the seven patients with acute pancreatitis in four families. All of them presented the symptoms before 28 years old and had pancreatic calcification. But the N21I mutation in exon 2 was detected in no families. And we did not find other changes in the trypsinogen gene. We could diagnose the hereditary pancreatitis through the trypsiongen gene mutation in only one pancreatitis patient regardless of the age of onset and number of patients in the family. This study revealed that the trypsinogen gene mutation in exon 3 was common and an important factor in Japanese hereditary pancreatitis, as in Caucasians. Conclusively, the trypsin plays a major role in the pathogenesis of pancreatitis.