A&R:PSMD12 的单倍体不足导致蛋白酶体功能障碍和亚临床自身炎症

2022-06-24 MedSci原创 MedSci原创

该研究表明,除了神经发育障碍外,PSMD12(编码Rpn5,是蛋白酶体的19S调节亚基)单倍体不足还会导致一系列炎症特征,该研究工作扩展了蛋白酶体相关的自身炎症综合征(PRAAS) 的基因型和表型谱。

目的蛋白酶体相关的自身炎症综合征(PRAAS) 的临床特征是反复发热、中性粒细胞性皮肤病、脂肪营养不良、关节挛缩和发育迟缓。PRAAS是由影响蛋白酶体成分的突变和I型干扰素(IFN)通路的激活引起的。PSMD12编码52.9 kd的蛋白质,Rpn5,是蛋白酶体的19S调节亚基,可促进捕获的底物的去泛素化。本研究旨在调查一种新发现的由PSMD12单倍体不足引起的PRAAS类型的致病机制。

方法对患有皮疹、先天性葡萄膜炎和发育迟缓的家庭成员进行了全外显子组测序。来自浙江的研究人员进行了功能研究以评估患者的蛋白酶体功能障碍和炎症特征,并进行单细胞RNA测序以进一步探索免疫细胞活化的范围。

结果2个家族成员中发现了一个新的PSMD12截断变异 (c.865C>T, p.Arg289*)在外周血单个核细胞(PBMC)以及PSMD12敲低HEK 293T细胞系中发现蛋白酶体功能受损。此外,通过单细胞RNA测序确定了患者PBMC中的炎症特征,并发现了升高的IFN信号,尤其是在单核细胞中。来自患者的CD14+经典单核细胞和CD16+非经典单核细胞在IIFN通路中的基因表达升高。

结论这些发现表明,除了神经发育障碍外,PSMD12单倍体不足还会导致一系列炎症特征。该研究工作扩展了PRAAS的基因型和表型谱,并提出了大多数PRAAS患者几乎特有的炎症表型与先前报道的Stankiewicz-Isidor综合征中近乎独特的神经发育表型之间的桥梁。

出处:Yan, K., Zhang, J., Lee, P.Y., Tao, P., Wang, J., Wang, S., Zhou, Q. and Dong, M. (2022), Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation. Arthritis Rheumatol, 74: 1083-1090. https://doi.org/10.1002/art.42070

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    2022-11-05 canlab
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    2022-06-23 jingjing

    大家一般关心疾病,但是亚临床更重要,这是疾病防控方向的前移,各类疾病都是这样。如亚临床甲减,亚临床心肌损伤,亚临床心衰等

    0

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