Study on molecular mechanism underlying genomic susceptibility to congenital hypomyelinating leukodystrophy

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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.