Sándor Máté, Vitale David S, Nagy Zoltán Attila, Ibrahim Sherif Y, Abu-El-Haija Maisam, Lazou Maria, Vajda Sandor, Sahin-Tóth Miklós
Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Pancreatology. 2025 Feb;25(1):70-81. doi: 10.1016/j.pan.2024.12.013. Epub 2024 Dec 24.
BACKGROUND/OBJECTIVES: Genetic variants in PRSS1 encoding human cationic trypsinogen are associated with hereditary pancreatitis. The clinically frequent variants exert their pathogenic effect by increasing intrapancreatic trypsin activity, while a distinct subset of variants causes disease via mutation-induced trypsinogen misfolding and endoplasmic reticulum (ER) stress. Here, we report a novel misfolding PRSS1 variant.
We used next-generation and Sanger sequencing to screen the index patient. We performed structural modeling and analyzed the functional effects of the PRSS1 variant.
A heterozygous c.182C>T (p.Ala61Val) PRSS1 variant was identified in a case of suspected intrauterine pancreatitis with pseudocyst formation. Recombinant p.Ala61Val trypsinogen autoactivated to lower trypsin levels, but activity of p.Ala61Val trypsin was similar to wild type. In cell culture experiments, the variant exhibited reduced secretion and intracellular retention. Cells expressing the p.Ala61Val variant showed signs of ER stress, as judged by elevated mRNA expression of Hspa5 encoding the chaperone BiP, and increased mRNA splicing of the transcription factor XBP1.
Taken together, the observations expand the repertoire of misfolding PRSS1 variants and highlight the need for functional analysis to identify this rare form of genetic etiology.
背景/目的：编码人阳离子胰蛋白酶原的PRSS1基因变异与遗传性胰腺炎相关。临床上常见的变异通过增加胰腺内胰蛋白酶活性发挥致病作用，而另一类不同的变异则通过突变诱导的胰蛋白酶原错误折叠和内质网（ER）应激导致疾病。在此，我们报告一种新的错误折叠PRSS1变异。
我们使用下一代测序和桑格测序对索引患者进行筛查。我们进行了结构建模并分析了PRSS1变异的功能效应。
在一例疑似宫内胰腺炎伴假性囊肿形成的病例中鉴定出杂合的c.182C>T（p.Ala61Val）PRSS1变异。重组的p.Ala61Val胰蛋白酶原自动激活至较低的胰蛋白酶水平，但p.Ala61Val胰蛋白酶的活性与野生型相似。在细胞培养实验中，该变异表现出分泌减少和细胞内滞留。通过编码伴侣蛋白BiP的Hspa5的mRNA表达升高以及转录因子XBP1的mRNA剪接增加判断，表达p.Ala61Val变异的细胞显示出内质网应激的迹象。
综上所述，这些观察结果扩展了错误折叠PRSS1变异的范围，并强调了进行功能分析以识别这种罕见遗传病因形式的必要性。
