PDF(Pubmed)
Abstract：
OBJECTIVE: Studies of a rare homozygous missense mutation identified in two brothers diagnosed with congenital pancreatic lipase deficiency (CPLD) provided the first definitive evidence linking CPLD with missense mutations in the gene of PNLIP. Herein, we investigated the molecular basis for the loss-of-function in the three novel PNLIP variants (c.305G > A, p.(W102∗); c.562C > T, p.(R188C); and c.1257G > A, p.(W419∗)) associated with CPLD.
METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress.
RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress.
CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.
METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress.
RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress.
CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.
摘要：
目的：在诊断为先天性胰腺脂肪酶缺乏症（CPLD）的两个兄弟中发现了一种罕见的纯合错义突变的研究提供了第一个明确的证据，将CPLD与PNLIP基因的错义突变联系起来。在这里，我们研究了三种新型PNLIP变体中功能丧失的分子基础(c.305G>A，p.(W102*)；c.562C>T，p.(R188C)；和c.1257G>A，p.(W419＊))与CPLD相关。
方法：我们通过评估三种新的PNLIP变体在转染细胞中的分泌特性，细胞内分布，和内质网（ER）应激的标志物。
结果：所有三种变体都有分泌缺陷。值得注意的是,p.R188C和p.W419*变体诱导PNLIP的错误折叠，并作为洗涤剂不溶性聚集体积累，导致蛋白质和mRNA水平的BiP升高，表明ER应激增加。
结论：所有三种新型PNLIP变异体均通过分泌受损导致功能丧失。此外,p.R188C和p.W419*变体可能通过错误折叠诱导蛋白毒性，并可能增加胰腺腺泡细胞损伤的风险。
方法：我们通过评估三种新的PNLIP变体在转染细胞中的分泌特性，细胞内分布，和内质网（ER）应激的标志物。
结果：所有三种变体都有分泌缺陷。值得注意的是,p.R188C和p.W419*变体诱导PNLIP的错误折叠，并作为洗涤剂不溶性聚集体积累，导致蛋白质和mRNA水平的BiP升高，表明ER应激增加。
结论：所有三种新型PNLIP变异体均通过分泌受损导致功能丧失。此外,p.R188C和p.W419*变体可能通过错误折叠诱导蛋白毒性，并可能增加胰腺腺泡细胞损伤的风险。
