<br>单核细胞可塑性缺陷和 cAMP 通路改变是 USB1 突变的异皮病伴中性粒细胞减少症 Clericuzio 型的特征,British Journal of Haematology

当前位置： X-MOL 学术 › Br. J. Haematol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

单核细胞可塑性缺陷和 cAMP 通路改变是 USB1 突变的异皮病伴中性粒细胞减少症 Clericuzio 型的特征
British Journal of Haematology ( IF 5.1 ) Pub Date : 2023-10-01 , DOI: 10.1111/bjh.19128
Prahlad Parajuli _{1,

2} , Douglas B Craig _{2,

3} , Manisha Gadgeel _{4,

5} , Shruti Bagla ₃ , Robert E Wright ₁ , Roland Chu _{4,

5} , Christina M Shanti ₄ , Rajeev Thirunagari ₄ , Sudershan K Grover ₄ , Yaddanapudi Ravindranath _{2,

3,

4}

Affiliation

伴有中性粒细胞减少症 (PN) 克莱里库齐奥型 (OMIM #604173) 的皮肤异色病是一种罕见疾病，其皮肤色素沉着过度和色素减退是由双等位基因USB1变异引起的。目前的研究是由于一名患有 c.266-1G>A (p.E90Sfster8) 突变纯合子的受影响儿童的肛周撕裂伤口愈合不良而引发的，该儿童来自先前报道的一个家庭。 G-CSF/CSF3 或 GM-CSF/CSF2 治疗可暂时增加中性粒细胞/单核细胞计数，但对伤口愈合没有影响。外周血分析显示，受影响的两兄弟缺乏与全身炎症细胞因子谱相关的非经典（CD14 ^+/- CD16 ⁺ ）单核细胞。重要的是，尽管同源受体表达正常，但根据细胞因子分泌或 CD16 表达确定，PN 患者的单核细胞在体外对 M-CSF 或 IL-34 没有反应。单核细胞的 RNAseq 显示 293 个差异表达基因，包括与白细胞分化和环磷酸腺苷 (cAMP) 信号传导相关的GATA2 、 AKAP6和PDE4DIP显着下调。值得注意的是，PN 患者的血浆 cAMP 明显较低。我们的研究揭示了 PN 与非经典单核细胞群缺乏之间的新关联。单核细胞可塑性的缺陷可能导致 PN 的疾病表现，而 cAMP 信号传导缺陷可能是USB1突变引起的剪接错误的主要影响。

"点击查看英文标题和摘要"

Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14^+/−CD16⁺) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.

更新日期：2023-10-01

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南