Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females
Genomic rearrangements resulting in PLP1 deletion occur by nonhomologous end joining and cause different dysmyelinating phenotypes in males and females
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DOI：
10.1086/342728
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发表时间：
2002-10-01
影响因子：
9.8
通讯作者：
Lupski, JR
中科院分区：
文献类型：
--
作者：
Inoue, K;Osaka, H;Lupski, JR
在大多数Pelizaeus-Merzbacher病患者中，蛋白脂质蛋白基因PLP 1的重复是负责的，而PLP 1的缺失是罕见的。这些亚显微染色体重排的基因组机制仍然未知。我们确定了三个家庭与PLP 1缺失（包括一个家庭在其他地方描述），产生了三个不同的过程。在一个家庭中，PLP 1缺失是由于整个PLP 1基因在19号染色体的端粒中发生了母体平衡的亚显微插入易位。由于位置效应，19 qtel上的PLP 1可能是无活性的，因为健康的男性同胞携带与正常X染色体相同的der（19）染色体沿着。缺失片段的基因组定位显示，缺失小于大多数PLP 1重复，仅涉及两个其他基因。我们假设这种缺失是罕见的，因为只有较小的缺失可以避免导致不育或致死。缺失断裂点两侧的DNA序列分析显示，在易位的家庭中的Alu-Alu重组。在其他两个家庭，没有同源序列侧翼的断点被发现，但远端断点嵌入在新的低拷贝重复，这表明基因组结构在刺激这些重排的潜在参与。在一个家庭中，连接序列揭示了一个复杂的重组事件。我们的数据表明，PLP 1缺失可能是由非同源末端连接。
In the majority of patients with Pelizaeus-Merzbacher disease, duplication of the proteolipid protein gene PLP1 is responsible, whereas deletion of PLP1 is infrequent. Genomic mechanisms for these submicroscopic chromosomal rearrangements remain unknown. We identified three families with PLP1 deletions (including one family described elsewhere) that arose by three distinct processes. In one family, PLP1 deletion resulted from a maternal balanced submicroscopic insertional translocation of the entire PLP1 gene to the telomere of chromosome 19. PLP1 on the 19qtel is probably inactive by virtue of a position effect, because a healthy male sibling carries the same der(19) chromosome along with a normal X chromosome. Genomic mapping of the deleted segments revealed that the deletions are smaller than most of the PLP1 duplications and involve only two other genes. We hypothesize that the deletion is infrequent, because only the smaller deletions can avoid causing either infertility or lethality. Analyses of the DNA sequence flanking the deletion breakpoints revealed Alu-Alu recombination in the family with translocation. In the other two families, no homologous sequence flanking the breakpoints was found, but the distal breakpoints were embedded in novel low-copy repeats, suggesting the potential involvement of genome architecture in stimulating these rearrangements. In one family, junction sequences revealed a complex recombination event. Our data suggest that PLP1 deletions are likely caused by nonhomologous end joining.