Wang Qi-Wen, Zou Wen-Bin, Masson Emmanuelle, Férec Claude, Liao Zhuan, Chen Jian-Min
Department of Gastroenterology, Changhai Hospital; National Key Laboratory of Immunity and Inflammation, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
Shanghai Institute of Pancreatic Diseases, Shanghai, China.
Hum Genomics. 2025 Mar 26;19(1):32. doi: 10.1186/s40246-025-00740-x.
Serine peptidase inhibitor, Kazal type 1 (SPINK1), a 56-amino-acid protein in its mature form, was among the first pancreatic enzymes to be extensively characterized biochemically and functionally. Synthesized primarily in pancreatic acinar cells and traditionally known as pancreatic secretory trypsin inhibitor, SPINK1 protects the pancreas by inhibiting prematurely activated trypsin. Since 2000, interest in SPINK1 has resurged following the discovery of genetic variants linked to chronic pancreatitis (CP). This review provides a historical overview of SPINK1's discovery, function, and gene structure before examining key genetic findings. We highlight three variants with well-characterized pathogenic mechanisms: c.-4141G > T, a causative enhancer variant linked to the extensively studied p.Asn34Ser (c.101A > G), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module; c.194 + 2T > C, a canonical 5' splice site GT > GC variant that retains 10% of wild-type transcript production; and an Alu insertion in the 3'-untranslated region, which causes complete loss of function by forming extended double-stranded RNA structures with pre-existing Alu elements in deep intronic regions. We emphasize the integration of a full-length gene splicing assay (FLGSA) with SpliceAI's predictive capabilities, establishing SPINK1 the first disease gene for which the splicing impact of all possible coding variants was prospectively determined. Findings from both mouse models and genetic association studies support the sentinel acute pancreatitis event (SAPE) model, which explains the progression from acute pancreatitis to CP. Additionally, SPINK1 variants may contribute to an increased risk of pancreatic ductal adenocarcinoma (PDAC). Finally, we discuss the therapeutic potential of SPINK1, particularly through adeno-associated virus type 8 (AAV8)-mediated overexpression of SPINK1 as a strategy for treating and preventing pancreatitis, and highlight key areas for future research.
丝氨酸蛋白酶抑制剂Kazal型1（SPINK1）成熟形式为含56个氨基酸的蛋白质，是最早在生物化学和功能方面得到广泛表征的胰腺酶之一。SPINK1主要在胰腺腺泡细胞中合成，传统上称为胰腺分泌型胰蛋白酶抑制剂，它通过抑制过早激活的胰蛋白酶来保护胰腺。自2000年以来，随着与慢性胰腺炎（CP）相关的基因变异的发现，人们对SPINK1的兴趣再度兴起。本综述在审视关键基因研究结果之前，对SPINK1的发现、功能和基因结构进行了历史概述。我们重点介绍了三种具有明确致病机制的变异：c.-4141G＞T，一种与广泛研究的p.Asn34Ser（c.101A＞G）相关的致病性增强子变异，该变异破坏了进化保守的HNF1A-PTF1L顺式调控模块内的一个PTF1L结合位点；c.194+2T＞C，一种典型的5'剪接位点GT＞GC变异，可保留10%的野生型转录本产生；以及3'非翻译区的一个Alu插入，它通过与内含子深处预先存在的Alu元件形成延伸的双链RNA结构导致功能完全丧失。我们强调将全长基因剪接分析（FLGSA）与SpliceAI的预测能力相结合，确定SPINK1是第一个前瞻性确定所有可能编码变异的剪接影响的疾病基因。小鼠模型和基因关联研究的结果都支持哨兵急性胰腺炎事件（SAPE）模型，该模型解释了从急性胰腺炎到CP的进展。此外，SPINK1变异可能会增加胰腺导管腺癌（PDAC）的风险。最后，我们讨论了SPINK1的治疗潜力，特别是通过8型腺相关病毒（AAV8）介导的SPINK1过表达作为治疗和预防胰腺炎的策略，并强调了未来研究的关键领域。
