Suganuma Tamaki, Hassan Huzaifa, Gogol Madelaine, Workman Jerry L
Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO 64110, USA.
NAR Mol Med. 2024 Oct 10;1(4):ugae015. doi: 10.1093/narmme/ugae015. eCollection 2024 Oct.
Increasing incidence of Fragile X disorders (FXD) and of immune-mediated disorders in FXD suggests that additional factors besides mutations contribute to the pathogenesis. Here, we discovered that the expression levels or splicing of specific transposon element (TE)-derived genes, regulating purine metabolism and immune responses against viral infections are altered in FXD. These genes include HLA genes clustered in chr6p21.3 and viral responsive genes in chr5q15. Remarkably, these TE-derived genes contain a low A T/C G suggesting base substitutions of A T to C G. The TE-derived genes with changed expression levels contained a higher content of 5'-CG-3' dinucleotides in FXD compared to healthy donors. This resembles the genomes of some RNA viruses, which maintain high contents of CG dinucleotides to sustain their latent infection exploiting antiviral responses. Thus, past viral infections may have persisted as TEs, provoking immune-mediated disorders in FXD.
脆性X障碍（FXD）的发病率不断上升，且FXD中免疫介导性疾病的发病率也不断上升，这表明除了突变之外，其他因素也参与了发病机制。在这里，我们发现，在FXD中，调节嘌呤代谢和针对病毒感染的免疫反应的特定转座子元件（TE）衍生基因的表达水平或剪接发生了改变。这些基因包括位于6号染色体p21.3区域的HLA基因簇和位于5号染色体q15区域的病毒反应基因。值得注意的是，这些TE衍生基因的A/T与C/G比例较低，提示存在A/T到C/G的碱基替换。与健康供体相比，FXD中表达水平发生变化的TE衍生基因含有更高含量的5'-CG-3'二核苷酸。这类似于一些RNA病毒的基因组，这些病毒通过利用抗病毒反应来维持高含量的CG二核苷酸以维持其潜伏感染。因此，过去的病毒感染可能以TE的形式持续存在，从而引发FXD中的免疫介导性疾病。
