de Boer Martin, van Leeuwen Karin, Geissler Judy, Weemaes Corry M, van den Berg Timo K, Kuijpers Taco W, Warris Adilia, Roos Dirk
Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, 1066 CX, The Netherlands.
Hum Mutat. 2014 Apr;35(4):486-96. doi: 10.1002/humu.22519. Epub 2014 Feb 24.
Retrotransposon-mediated insertion of a long interspersed nuclear element (LINE)-1 or an Alu element into a human gene is a well-known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X-chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA.
逆转录转座子介导的长散在核元件（LINE）-1或Alu元件插入人类基因是一种众所周知的致病机制。我们报告了一种新型的LINE-1介导的转录本从3号染色体上的TMF1基因插入到X染色体上的CYBB基因的事件。在一名患有慢性肉芽肿病的荷兰男性患者中，在CYBB的第1内含子中鉴定出一个5.8kb、不完整且部分外显子化的TMF1转录本，其方向与宿主基因相反。插入序列显示出逆转录转座事件的特征，具有反义多聚腺苷酸尾、靶位点重复和一个共有LINE-1内切酶切割位点。这种插入导致CYBB mRNA异常剪接，在CYBB的第1和第2外显子之间包含一个额外的117bp外显子。这个额外的外显子包含一个提前的终止密码子。逆转录转座发生在患者母亲胎儿发育的早期阶段，因为她表现出体细胞嵌合现象，而其父母的DNA中不存在这种突变。然而，突变等位基因在患者母亲中未表达，因为该插入仅在她DNA的甲基化部分中被发现。
