Abstract：
The NFE2L1 transcription factor (also known as Nrf1 for nuclear factor erythroid 2-related factor-1) is a broadly expressed basic leucine zipper protein that performs a critical role in the cellular stress response pathway. Here, we identified a heterozygous nonsense mutation located in the last exon of the gene that terminates translation prematurely, resulting in the production of a truncated peptide devoid of the carboxyl-terminal region containing the DNA-binding and leucine-zipper dimerization interface of the protein. Variant derivatives were well expressed in vitro, and they inhibited the transactivation function of wild-type proteins in luciferase reporter assays. Our studies suggest that this dominant-negative effect of truncated variants is through the formation of inactive heterodimers with wild-type proteins preventing the expression of its target genes. These findings suggest the potential role of diminished NFE2L1 function as an explanation for the developmental delay, hypotonia, hypospadias, bifid scrotum, and failure to thrive observed in the patient.
摘要：
NFE2L1转录因子（也称为核因子红系2相关因子1的Nrf1）是一种广泛表达的碱性亮氨酸拉链蛋白，在细胞应激反应途径中起关键作用。这里,我们发现了一个位于基因最后一个外显子的杂合子无义突变，它过早终止翻译，导致产生截短的肽，该肽没有包含蛋白质的DNA结合和亮氨酸拉链二聚化界面的羧基末端区域。变体衍生物在体外表达良好，在荧光素酶报告基因测定中，它们抑制了野生型蛋白的反式激活功能。我们的研究表明，截短变体的这种显性负效应是通过形成无活性的异二聚体，野生型蛋白阻止其靶基因的表达。这些发现表明NFE2L1功能减弱的潜在作用是对发育迟缓的解释。低张力,尿道下裂,阴囊双裂,在病人身上观察到未能茁壮成长。
