Study on molecular mechanism underlying genomic susceptibility to congenital hypomyelinating leukodystrophy

Pelizaeus-Merzbacher病(PMD)是一种以中枢神经系统髓鞘功能减退为特征的遗传性顽固性疾病。含有PLP1基因的基因组重复是PMD最常见的原因。然而，为什么重复是PMD最常见的原因尚不清楚。我们推测，可能存在一种基因组结构特征，使该基因组区域易于发生基因组重排。我们通过应用大量来自PLP1重复患者的DNA样本进行高分辨率基因组分析来验证这一假设，以描绘导致PLP1重复的异常基因组重排的分子机制。我们设计了一种针对PLP1基因组区域的高分辨率定制计算全息阵列，并分析了70例存在重复的PMD病例。我们在所有病例中都证实了涉及PLP1的基因组复制。复制的线段在长度和区域上各不相同。在近端和远端的断裂点中都没有发现共同的断裂点，尽管远端的断裂点倾向于聚集在几千kb的区域内，这些区域富含节段重复。我们还发现，在某些情况下，单拷贝或三拷贝片段中断了复制，这表明了基因组重排背后的复杂机制。我们正在核苷酸水平上检测这些案例中的重组连接片段。

Pelizaeus-Merzbacher disease (PMD) is inherited intractable disorder characterized by hypomyelination of central nervous system. Genomic duplication containing PLP1 gene is the most common cause of PMD. However, it is unknown as to why duplication is the most common cause of PMD. We hypothesized that there may be a genomic structural feature that predispose this genomic region for susceptibility of genomic rearrangement. We tested this hypothesis by applying numerous DNA samples from PLP1 duplication patients for high-resolution genomic analysis to delineate molecular mechanism underlying the abnormal genomic rearrangement resulting in PLP1 duplication. We designed a high-resolution custom CGH array specific to the PLP1 genomic region and analyzed 70 PMD cases with duplication. We confirmed genomic duplications involving PLP1 in all cases. Duplicated segments vary in length and region. No common breakpoint was found in either proximal or distal breakpoints, although distal breakpoints tend to cluster within a few thousands kb region enriched with segmental duplication. We also found interruption of duplication by single copy or triplicated copy segments in some cases, indicating a complex mechanism underlying genomic rearrangement. We are examining the recombination junction fragments in these cases at the nucleotide level.