Abstract：
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.
摘要：
嗜中性粒细胞减少症（PN）Clericuzio型（OMIM＃604173）是一种罕见的疾病，由双等位基因USB1变体引起的皮肤色素沉着过度和色素沉着不足。目前的研究是由于一名受影响的纯合子儿童的肛周撕裂伤口愈合不良而引起的，约为266-1G>A（p。E90Sfster8）突变，以前报道的一个家庭。用G-CSF/CSF3或GM-CSF/CSF2处理瞬时增加嗜中性粒细胞/单核细胞计数,而对伤口愈合没有影响。外周血分析显示缺乏非经典（CD14+/-CD16+）单核细胞，与全身性炎症细胞因子谱相关，两个受影响的兄弟。重要的是,尽管同源受体表达正常，来自PN患者的单核细胞在体外对M-CSF或IL-34无反应，如通过细胞因子分泌或CD16表达所确定的。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）信号相关的GATA2，AKAP6和PDE4DIP的显着下调。值得注意的是,PN患者血浆cAMP水平明显较低。我们的研究揭示了PN与缺乏非经典单核细胞群体的新关联。单核细胞可塑性的缺陷可能导致PN的疾病表现，而缺陷的cAMP信号传导可能是由USB1突变引起的剪接错误的主要作用。
