Genomic Rearrangements Resulting in PLP1 Deletion Occur by Nonhomologous End Joining and Cause Different Dysmyelinating Phenotypes in Males and Females

Abstract

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.

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

“…33 Duplications within the human genome are increasingly recognized as a cause of neurodegenerative phenotypes. Such rearrangements are responsible not only for Mendelian traits such as Charcot-Marie-Tooth neuropathy type 1A 39 and Pelizaeus-Merzbacher leukodystrophy, 40,41 but also for conditions generally thought to be acquired in nature such as Parkinson 42 and Alzheimer 43 diseases. Recurrent rearrangements in Charcot-Marie-Tooth neuropathy type 1A are mediated by nonallelic homologous recombination, 44 wherein genome architectural features seem to lead to genomic instability.…”

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki–Shaffer syndrome

“…35 -37 Although the deletion mechanism is not known in PSS, the highly variable breakpoints and range of deletion sizes suggest nonallelic homologous recombination through flanking repeats is likely not the mechanism through which these deletions occur. 38 Delineation of the breakpoint sequences may elucidate sequences susceptible to chromosome rearrangements and the mechanism causing these interstitial deletions.…”

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

“…A majority of PMD cases (70%) are caused by duplications of the PLP1 locus and manifest with classic PMD of mild to moderate severity. 7 Rare triplications (<1%) cause severe connatal disease, whereas full gene deletions (1%-2%) are associated with mild, late-onset symptoms, often termed ''null syndrome'' 18,[33][34][35][36] (also see GeneReviews in Web Resources). Additionally, over 200 unique point mutations have been identified in individuals (25%) presenting with PMD across the entire range of severity.…”