Daddali Ravindra, Kettunen Kaisa, Turunen Tanja, Knox Ainsley V C, Laine Pia, Chowdhury Iftekhar, Vänttinen Markku, Mamia Nanni, Stiegler Amy L, Boggon Titus J, Kere Juha, Romberg Neil, Seppänen Mikko R J, Varjosalo Markku, Martelius Timi, Grönholm Juha
Translational Immunology Research Program, University of Helsinki, Helsinki, Finland.
Laboratory of Genetics, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Clin Immunol. 2025 Aug;277:110503. doi: 10.1016/j.clim.2025.110503. Epub 2025 Apr 26.
PU.1 is an Ets family transcription factor crucial for hematopoietic cell fate. Complete PU.1 deficiency lethally arrests lympho- and myelopoiesis in mice. Individuals with SPI1 heterozygous loss-of-function variants exhibit disrupted gene expression patterns associated with B cell development. We identified the vertical transmission of a heterozygous SPI1c.538C>T p.(L180F) variant in a Finnish family. The index patient and his mother had severe bacterial infections, agammaglobulinemia, and low myeloid and plasmacytoid dendritic cell counts. The variant carrier sister had slightly reduced B cell counts, isolated IgA deficiency, and reduced dendritic cell counts. All individuals had diminished PU.1 protein expression in monocytes. In vitro studies showed that PU.1 L180F variant is less expressed and predominantly located in the cytoplasm. PU.1 WT mainly interacts with chromatin and centrosome-associated proteins, while the L180F variant showed fewer interactions. Our findings describe a novel PU.1 variant leading to agammaglobulinemia with variable penetrance.
PU.1是一种对造血细胞命运至关重要的Ets家族转录因子。PU.1完全缺乏会导致小鼠淋巴细胞生成和髓细胞生成致命性停滞。携带SPI1功能丧失杂合变体的个体表现出与B细胞发育相关的基因表达模式紊乱。我们在一个芬兰家族中发现了杂合SPI1c.538C>T p.(L180F)变体的垂直传播。先证者及其母亲患有严重细菌感染、无丙种球蛋白血症，且髓样和浆细胞样树突状细胞计数较低。变体携带者姐妹的B细胞计数略有减少、孤立性IgA缺乏且树突状细胞计数减少。所有个体的单核细胞中PU.1蛋白表达均降低。体外研究表明，PU.1 L180F变体表达较少，主要位于细胞质中。PU.1野生型主要与染色质和中心体相关蛋白相互作用，而L180F变体的相互作用较少。我们的研究结果描述了一种导致具有可变外显率的无丙种球蛋白血症的新型PU.1变体。
