Missense mutation in selenocysteine synthase causes cardio-respiratory failure and perinatal death in mice which can be compensated by selenium-independent GPX4.
Missense mutation in selenocysteine synthase causes cardio-respiratory failure and perinatal death in mice which can be compensated by selenium-independent GPX4.
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DOI：
10.1016/j.redox.2021.102188
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发表时间：
2021-11-12
期刊：
影响因子：
11.4
通讯作者：
Schweizer U
中科院分区：
文献类型：
--
作者：
Fradejas-Villar N;Zhao W;Reuter U;Doengi M;Ingold I;Bohleber S;Conrad M;Schweizer U
硒蛋白是一小类蛋白质，含有微量元素硒，其形式为稀有氨基酸硒半胱氨酸(Sec)，由UGA密码子解码。在人类中，已经鉴定出编码不同的硒蛋白或硒蛋白生物合成因子的基因的一些致病变体。硒半胱氨酸合成酶(SEPSECS)催化SEC-tRNA[Ser]SEC生物合成的最后一步，其致病变异在进行性小脑萎缩的儿童中有报道。为了了解SEPSECS缺陷的相关病理机制，我们建立了一个新的小鼠模型，该模型概括了小鼠Sepsecs基因(SepsecsY334C)中各自的人类致病P.Y334C变体。与患者不同，携带p.Y334C变异纯合子的幼崽在围产期死亡，并有心肺衰竭的迹象。围产期死亡让人想起人类的Sedaghatian脊柱干骺端发育不良症，这种疾病是由编码硒蛋白和关键的铁下垂调节因子谷胱甘肽过氧化物酶4(Gpx4)的基因的致病变异引起的。在SepsecsY334C/Y334C小鼠中，不同的硒蛋白的蛋白表达水平被发现在大脑和分离的皮质神经元中普遍降低，而转录组学分析发现NRF2调节的基因上调。SepsecsY334C/Y334C小鼠与Gpx4中催化活性SEC对Cys有靶向性突变的小鼠杂交挽救了SepsecsY334C/Y334C小鼠的围产期死亡，表明SepsecsY334C/Y334C小鼠的心肺功能缺陷是由于缺乏Gpx4引起的。与SepsecsY334C/Y334C小鼠一样，在这些复合突变小鼠中，硒蛋白表达水平保持低水平，NRF2调节基因保持高表达，表明非硒Gpx4加上持续的抗氧化反应足以补偿功能障碍的SEC-tRNA[Ser]SEC生物合成。我们的发现表明，SEPSECS或Gpx4致病变异的儿童甚至可能受益于不完全补偿Gpx4活性受损的治疗。Y334C/Y334C小鼠出生后出现心肺衰竭。这些小鼠类似于Gpx4(塞达格氏病)纯合子突变的患者。Y334C/Y334C小鼠可通过表达不依赖于硒的Gpx4而获救。如果Gpx4不是限制性的，其他硒蛋白的缺乏是可以容忍的。NRF2调控基因在SepsecsY334C/Y334C小鼠心脏和脑中的上调。
Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic variants in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic variants in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA[Ser]Sec biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the pathomechanism associated with SEPSECS deficiency, we generated a novel mouse model recapitulating the respective human pathogenic p.Y334C variant in the murine Sepsecs gene (SepsecsY334C). Unlike in patients, pups homozygous for the p.Y334C variant died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by pathogenic variants in the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in SepsecsY334C/Y334C mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of SepsecsY334C/Y334C mice with mice harboring a targeted mutation of the catalytically active Sec to Cys in GPX4 rescued perinatal death of SepsecsY334C/Y334C mice, showing that the cardio-respiratory defects of SepsecsY334C/Y334C mice were caused by the lack of GPX4. Like in SepsecsY334C/Y334C mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA[Ser]Sec biosynthesis. Our findings imply that children with pathogenic variants in SEPSECS or GPX4 may even benefit from treatments that incompletely compensate for impaired GPX4 activity. SepsecsY334C/Y334C mice show cardio-respiratory failure after birth. These mice resemble patients with homozygous mutations in GPX4 (Sedaghatian disease). SepsecsY334C/Y334C mice can be rescued by expression of a selenium-independent GPX4. Deficiency of other selenoproteins can be tolerated, if GPX4 is not limiting. Upregulation of NRF2-regulated genes in hearts and brains of SepsecsY334C/Y334C mice.
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