Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat-containing protein that uniquely associates with latent transforming growth factor beta-1 (TGF- β1) and anchors it on the cell surface; this anchoring is required for activation of TGF-β1 in macrophages and microglia. We report six individuals from four families with bi-allelic variants in NRROS. All affected individuals had neurodegenerative disease with refractory epilepsy, developmental regression, and reduced white matter volume with delayed myelination. The clinical course in affected individuals began with normal development or mild developmental delay, and the onset of seizures occurred within the first year of life, followed by developmental regression. Intracranial calcification was detected in three individuals. The phenotypic features in affected individuals are consistent with those observed in the Nrros knockout mouse, and they overlap with those seen in the human condition associated with TGF-β1 deficiency. The disease-causing NRROS variants involve two significant functional NRROS domains. These variants result in aberrant NRROS proteins with impaired ability to anchor latent TGF-β1 on the cell surface. Using confocal microscopy in HEK293T cells, we demonstrate that wild-type and mutant NRROS proteins co-localize with latent TGF-β1 intracellularly. However, using flow cytometry, we show that our mutant NRROS proteins fail to anchor latent TGF-β1 at the cell surface in comparison to wild-type NRROS. Moreover, wild-type NRROS rescues the defect of our disease-associated mutants in presenting latent TGF-β1 to the cell surface. Taken together, our findings suggest that loss of NRROS function causes a severe childhood-onset neurodegenerative condition with features suggestive of a disordered response to inflammation.

中文翻译：

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双等位基因LoF NRROS变体会破坏活性TGF-β1的传递，导致颅内钙化导致严重的婴幼儿发作性神经退行性疾病。

活性氧负调节剂（NRROS）是一种富含亮氨酸的重复序列蛋白，与潜在的转化生长因子β-1（TGF-β1）独特结合，并将其锚定在细胞表面。这种锚固是巨噬细胞和小胶质细胞中TGF-β1活化所必需的。我们报告了来自四个家庭的六个个体，它们在NRROS中具有双等位基因变异。所有受影响的个体均患有神经退行性疾病，伴有难治性癫痫，发育衰退，白质减少，髓鞘延迟。患病个体的临床病程始于正常发育或轻度发育延迟，癫痫发作在生命的第一年内发生，然后发育退化。在三个人中检测到颅内钙化。患病个体的表型特征与在Nrros基因敲除小鼠中观察到的特征一致，并且与在与TGF-β1缺乏症相关的人类疾病中观察到的特征重叠。引起疾病的NRROS变体涉及两个重要的功能NRROS结构域。这些变体导致异常的NRROS蛋白受损，从而无法将潜在的TGF-β1锚定在细胞表面。在HEK293T细胞中使用共聚焦显微镜，我们证明了野生型和突变型NRROS蛋白与潜在的TGF-β1在细胞内共定位。然而，使用流式细胞仪，我们显示，与野生型NRROS相比，我们的突变NRROS蛋白未能将潜在的TGF-β1锚定在细胞表面。此外，野生型NRROS可以将潜在的TGF-β1呈现给细胞表面，从而挽救了我们与疾病相关的突变体的缺陷。在一起