胰蛋白酶原基因缺失突变导致早发型自身免疫性相关的多器官多发囊肿的研究  

Trypsinogen gene deletion mutation causes early onset autoimmune related pulmonary bulla,hepatic multiple cysts

作　　者：徐志峰[1] 林寿榕[2] 刘奇才[2] 陈瑞庆[3] 林丽清[4] 翁少煌[4] 郜峰[5] 庄则豪[6] 陈金通[6] 

机构地区：[1]南京军区福州总医院附属第一医院普通外科,莆田市351100 [2]福建医科大学附属第一医院检验科,福州市350004 [3]福建医科大学附属第一医院肝病中心,福州市350004 [4]福建医科大学药学院,福州市350004 [5]福建医科大学附属第一医院病理科,福州市350004 [6]福建医科大学附属第一医院消化科,福州市350004

出　　处：《实用检验医师杂志》2014年第2期70-75,共6页Chinese Journal of Clinical Pathologist

基　　金：国家高新技术基础研究863计划(2012AA022604);福建省自然科学基金(2013J1023);福建省医学创新课题(2013-CXB-21);福建省高校杰出青年基金(JA12133)

摘　　要：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(setine 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.300_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。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.

关 键 词：自身免疫性胰腺炎 PRSS1基因 缺失突变 多囊性 多器官 

分 类 号：R576[医药卫生—消化系统]