【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.300₁304 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。更多还原

【Abstract】 Objective To identification of cationic trypsinogen（PRSS1） gene deletion mutation in autoimmune related multiple cysts and its pathogenic mechanism.Methods All exons and flanking intron shear region of pancreatitis and polycystic lesions related genes including PRSSI,cystic fibrosis transmembrane conductance regulator（CFTR）,serine protease inhibitor Kazal type 1（SPINK1）,protein kinase Dl（PKD1）and PKD2 were analyzed by DNA sequencing technology.The sequential variation of DNA and cDNA were detected.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 PRSSI gene were first found,and it generating activation peptide deletion trypsinogen with biological activity.The liver,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 PRSSI:c.1300₁304 del CCCAG is a new mutation causes early onset of autoimmune pancreatitis and it correlated with multiple organ cyst closely.更多还原