Sahin-Tóth M, Tóth M
Department of Physiology, University of California Los Angeles, Los Angeles, California 90095-1662, USA.
Biochem Biophys Res Commun. 2000 Nov 19;278(2):286-9. doi: 10.1006/bbrc.2000.3797.
Hereditary pancreatitis (HP), an autosomal dominant disorder, has been associated with mutations in the cationic trypsinogen gene. Here we demonstrate that the two most frequent HP mutations, Arg117 --> His and Asn21 --> Ile, significantly enhance autoactivation of human cationic trypsinogen in vitro, in a manner that correlates with the severity of clinical symptoms in HP. In addition, mutation Arg117 --> His inhibits autocatalytic inactivation of trypsin, while mutation Asn21 --> Ile has no such effect. The findings strongly argue that increased trypsinogen activation in the pancreas is the common initiating step in both forms of HP, whereas trypsin stabilization might also contribute to HP associated with the Arg117 --> His mutation.
遗传性胰腺炎（HP）是一种常染色体显性疾病，与阳离子胰蛋白酶原基因突变有关。我们在此证明，两种最常见的HP突变，即精氨酸117突变为组氨酸（Arg117→His）和天冬酰胺21突变为异亮氨酸（Asn21→Ile），在体外能显著增强人阳离子胰蛋白酶原的自身激活，其方式与HP临床症状的严重程度相关。此外，精氨酸117突变为组氨酸（Arg117→His）的突变抑制了胰蛋白酶的自身催化失活，而天冬酰胺21突变为异亮氨酸（Asn21→Ile）的突变则无此作用。这些发现有力地表明，胰腺中胰蛋白酶原激活增加是两种形式HP的共同起始步骤，而胰蛋白酶的稳定化可能也与精氨酸117突变为组氨酸（Arg117→His）的突变相关的HP有关。
