Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS One. 2011;6(12):e29248. doi: 10.1371/journal.pone.0029248. Epub 2011 Dec 14.
We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.
我们最近报道了常染色体显性慢性黏膜皮肤念珠菌病（AD-CMC）的遗传病因是 STAT1 基因的突变。在本研究中，我们表明 STAT1 卷曲螺旋（CC）结构域中的 Arg274Trp 突变是三个患者家系中 AD-CMC 的遗传病因。克隆和转染实验表明，突变 STAT1 抑制了 IL12R/IL-23R 信号，STAT1 的过度磷酸化可能是潜在的分子机制。通过 IL-12 和 IL-23 的受体抑制信号传导会导致 Th1/Th17 反应明显减弱，从而导致真菌感染的易感性增加。未来的挑战是将这一知识转化为治疗这种严重免疫缺陷的新策略。
