汉族自身免疫性胰腺炎患者PRSS1基因新的移码突变的鉴定

Identification of a novel frame-shift mutation in PRSS1 gene in Han patients with autoimmune pancreatitis.

作者信息

Gao F, Li Y, Wang C, Zhuang Z, Liu Q C, Chen J, Hong G, Xu Z

机构信息

Department of Laboratory Medicine, the first Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.

出版信息

Curr Mol Med. 2014 Mar;14(3):340-8. doi: 10.2174/1566524013666131118114432.

DOI:10.2174/1566524013666131118114432

PMID:24236450

Abstract

OBJECTIVE

To detect mutations of trypsinogen gene (PRSS1) in patients with autoimmune pancreatitis (AIP) and to determine the underlying pathogenesis.

METHODS

DNA sequencing was used to detect full-length of PRSS1, cystic fibrosis transmembrane conductance regulator (CFTR), and pancreatic secretory trypsin inhibitor (SPINK1) genes mutations in an AIP family and a sporadic case and 520 normal controls. Furthermore, a mutant-expressing system was constructed for functional confirmation.

RESULTS

For the first time, we report a deletion mutation at exon 2 of PRSS1 gene (IVS 2 +56_60 del CCCAG) which encoded a truncated PRSS1 protein without trypsinogen activation peptide (TAP). Vitro functional study suggested the identified mutation would result in loss of PRSS1 activity. Mutant trypsinogen activated at a faster rate than wild-type trypsinogen in the autoactivation experiment. Histopathologic examination revealed the ratio of IgG4/IgG-positive plasma cells exceeded 0.455 in pancreas, and the patients responded to glucocorticoids.

CONCLUSION

PRSS1: IVS 2 +56_60 del CCCAG is a noval mutant which may contribute to AIP pathogenesis.

摘要

目的

检测自身免疫性胰腺炎（AIP）患者胰蛋白酶原基因（PRSS1）的突变情况，并确定其潜在发病机制。

方法

采用DNA测序技术检测一个AIP家系、1例散发病例及520名正常对照者的PRSS1、囊性纤维化跨膜传导调节因子（CFTR）和胰腺分泌性胰蛋白酶抑制剂（SPINK1）基因全长突变情况。此外，构建突变体表达系统进行功能验证。

结果

我们首次报道PRSS1基因第2外显子存在缺失突变（IVS 2 +56_60 del CCCAG），该突变编码一种无胰蛋白酶原激活肽（TAP）的截短型PRSS1蛋白。体外功能研究表明，所鉴定的突变会导致PRSS1活性丧失。在自激活实验中，突变型胰蛋白酶原比野生型胰蛋白酶原激活速度更快。组织病理学检查显示，胰腺中IgG4/IgG阳性浆细胞比例超过0.455，且患者对糖皮质激素治疗有反应。