CAJ | 학술논문

目的：探讨由胰蛋白酶原基因（cationic trypsinogen， PRSS1）突变引发的早发型自身免疫性相关的多器官多发囊肿及其致病机制。方法采用DNA全长测序技术分析PRSS1、囊性纤维化跨膜通道调节因子（cystic fibrosis transmembrane conductance regulator， CFTR）、丝氨酸蛋白酶抑制剂 Kazal 1型（serine protease inhibitor Kazal type 1， SPINK1）、蛋白激酶D（protein kinase D， PKD）1和PKD2等胰腺炎和多囊性病变相关基因的所有外显子及其侧翼内含子剪切区域，确定DNA和cDNA序列的变异，通过与家系内部和正常对照的比较分析，对检测到的变异是否与疾病相关进行探讨，并构建突变体表达体系进行功能学验证，同时对患者的肺、肝、胰腺等穿刺样本进行免疫组织化学和特殊染色。结果在2例年轻的自身免疫性胰腺炎患者中首次发现PRSS1基因2号外显子缺失突变生成激活肽缺失型的胰蛋白酶原，并具有生物学活性；肝脏、肺穿刺病理均可见不同程度的淋巴细胞和浆细胞浸润，肺组织病理显示弹力纤维、网状纤维明显减少；患者表现为多脏器多囊性病变，血清胰蛋白酶、弹力蛋白酶、AAT显著增高。使用糖皮质激素治疗有效。结论 PRSS1：c．1300_1304 del CCCAG是引发早发型自身免疫性胰腺炎的新突变形式，并与多器官囊肿关系密切。
목적：탐토유이단백매원기인（cationic trypsinogen， PRSS1）돌변인발적조발형자신면역성상관적다기관다발낭종급기치병궤제。방법채용DNA전장측서기술분석PRSS1、낭성섬유화과막통도조절인자（cystic fibrosis transmembrane conductance regulator， CFTR）、사안산단백매억제제 Kazal 1형（serine protease inhibitor Kazal type 1， SPINK1）、단백격매D（protein kinase D， PKD）1화PKD2등이선염화다낭성병변상관기인적소유외현자급기측익내함자전절구역，학정DNA화cDNA서렬적변이，통과여가계내부화정상대조적비교분석，대검측도적변이시부여질병상관진행탐토，병구건돌변체표체체계진행공능학험증，동시대환자적폐、간、이선등천자양본진행면역조직화학화특수염색。결과재2례년경적자신면역성이선염환자중수차발현PRSS1기인2호외현자결실돌변생성격활태결실형적이단백매원，병구유생물학활성；간장、폐천자병리균가견불동정도적림파세포화장세포침윤，폐조직병리현시탄력섬유、망상섬유명현감소；환자표현위다장기다낭성병변，혈청이단백매、탄력단백매、AAT현저증고。사용당피질격소치료유효。결론 PRSS1：c．1300_1304 del CCCAG시인발조발형자신면역성이선염적신돌변형식，병여다기관낭종관계밀절。
Objective To identification of cationic trypsinogen(PRSS1) gene deletion mutation in au-toimmune related multiple cysts and its pathogenic mechanism. Methods All exons and flanking intron shear region of pancreatitis and polycystic lesions related genes including PRSS1 , cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), protein kinase D1(PKD1) and PKD2 were analyzed by DNA sequencing technology. The sequential variation of DNA and cDNA were de-tected. Whether the variation associated with disease were detected by comparing with family inside and healthy controls. The mutant expression system was constructed and its functional verification was done. At the same time, immunohistochemical and special staining in patients with lung and liver pancreas biopsy samples were executed. Results In two patients with autoimmune pancreatitis, deletion mutant in exon 2 of PRSS1 gene were first found, and it generating activation peptide deletion trypsinogen with biological activity. The liv-er, lung was lymphocytic and plasma cell infiltration, elastic fibers and reticular fibers decreased the formation of multiple organ polycystic disease. Serum trypsin, elastase and alpha antitrypsin increased significantly. Use of glucocorticoid treatment was effective. Conclusion PRSS1:c.1300_1304 del CCCAG is a new mutation causes early onset of autoimmune pancreatitis and it correlated with multiple organ cyst closely.