Premature termination codon (PTC) mutations in the granulin gene (GRN) lead to loss-of-function (LOF) of the progranulin protein (PGRN), causing frontotemporal lobar degeneration (FTLD) by haploinsufficiency. GRN expression is regulated at multiple levels, including the 5’ untranslated region (UTR). The main 5’ UTR of GRN and an alternative 5’ UTR, contain upstream open reading frames (uORFs). These mRNA elements generally act as cis repressors of translation. Disruption of each uORF of the alternative 5’ UTR, increases protein expression with the two ATG-initiated uORFs being capable of initiating translation. We performed targeted sequencing of the uORF regions in a Flanders-Belgian cohort of patients with frontotemporal dementia (FTD) and identified two genetic variants, one in each 5’ UTR. Both variants increase downstream protein levels, with the main 5’ UTR variant rs76783532 causing a significant 1.5-fold increase in protein expression. We observed that the presence of functional uORFs in the alternative 5’ UTR act as potential regulators of PGRN expression and demonstrate that genetic variation within GRN uORFs can alter their function.

颗粒蛋白基因 ( GRN )中的过早终止密码子 (PTC) 突变导致颗粒蛋白前体蛋白 (PGRN) 功能丧失 (LOF)，导致单倍体不足导致额颞叶变性 (FTLD)。GRN表达在多个水平上受到调节，包括 5' 非翻译区 (UTR)。GRN的主要5'UTR和另一种 5' UTR，包含上游开放阅读框 (uORF)。这些 mRNA 元件通常充当翻译的顺式阻遏物。替代 5' UTR 的每个 uORF 的中断会增加蛋白质表达，两个 ATG 启动的 uORF 能够启动翻译。我们对法兰德斯-比利时额颞叶痴呆 (FTD) 患者队列中的 uORF 区域进行了靶向测序，并确定了两个遗传变异，每个 5' UTR 中都有一个。两种变体都增加了下游蛋白质水平，主要的 5' UTR 变体 rs76783532 导致蛋白质表达显着增加 1.5 倍。我们观察到替代 5' UTR 中功能性 uORF 的存在可作为 PGRN 表达的潜在调节因子，并证明GRN内的遗传变异uORF 可以改变它们的功能。