Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding.
Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding.
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DOI：
10.1002/humu.24105
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发表时间：
2020-11
期刊：
影响因子：
3.9
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Cassidy BM;Zino S;Fjeld K;Molven A;Lowe ME;Xiao X
遗传变异有助于成人和儿童慢性胰腺炎（CP）的风险。风险变异CEL- hyb1是CEL及其邻近假基因（CELP）的重组杂交等位基因，编码胰腺消化酶羧基酯脂肪酶（CEL）的致病变异。我们之前在CEL-HYB1的断点区域发现了两个非同义snp的组合，C . 1463t >C （p. Ile488Thr）和C . 1643c >T （p. Thr548Ile）。在此，我们测试了这些错义变体是否会改变CP风险及其对CEL-HYB1蛋白功能特性的影响。对欧洲患者和对照组的CEL-HYB1单倍型的检测显示，thr488 - ile548组合仅在病例中存在（p≤0.001）。纯化的重组CEL-HYB1变体的脂肪酶活性显示正常或接近正常。HEK293T细胞中表达的CEL- hyb变异均较CEL分泌减少，形成细胞内蛋白聚集，引发内质网应激。因此，我们提出，在CEL-HYB中存在的错义变体通过错误折叠和功能获得的蛋白质毒性增加了CEL-HYB1的致病性。有趣的是，在功能分析中，Thr488-Ile548和Thr488-Thr548具有相同的致病性，尽管在病例中只有Thr488-Ile548单倍型显著富集。对基因和功能数据不匹配的解释需要进一步调查。
Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p ≤ .001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation.
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