Characterization of a chromosomal duplication in the Plp1 locus: a new mouse model of Pelizaeus-merzbacher disease

Clark, Kristi
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University of Delaware
Pelizaeus-Merzbacher disease (PMD) is a rare, progressive, degenerative central nervous system disorder in which coordination, motor abilities, and intellectual function deteriorate. The disease is one of the leukodystrophies, a group of disorders that affect growth of the myelin sheath. It is caused by mutations of the proteolipid protein 1 gene (Plp1), which is located on the X chromosome and encodes the most abundant protein of myelin. About 50-75% of PMD cases are due to duplications of a region of the X chromosome that includes the entire Plp1 gene. The duplications are typically in a head-to-tail arrangement and they vary in size and gene content. Although rodent models have been developed, these models have Plp1 gene copies that range from two to fourteen, and none contain an actual genomic rearrangement that resemble those found in PMD patients. The mouse chromosome engineering resources (MICER) were used to generate the Plp1dup mouse model by introducing a duplication into the mouse genome that is similar to human duplications. The X chromosome duplication is 270 kb in size, which is within the size range of human duplications, and in addition to Plp1, it contains five other surrounding genes that are also commonly duplicated in PMD patients. In this work, the new mouse model was characterized, and it was concluded that a duplication that includes the entire Plp1 gene leads to a complex expression pattern of Plp1 and not just a simple overexpression. A duplication in the Plp1 locus alters the expression of Plp1 as well as four of the other five genes within the duplication. Mice with the genomic duplication also display altered expression in other important myelin proteins leading to a disruption in normal myelin formation. Our initial Plp1dup mice characterization studies have only begun to reveal how a duplication of the Plp1 locus results in a disease phenotype.