We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Gait Abnormalities and Progressive Myelin Degeneration in a New Murine Model of Pelizaeus-Merzbacher Disease with Tandem Genomic Duplication.
- Authors
Clark, Kristi; Sakowski, Lauren; Sperle, Karen; Banser, Linda; Landel, Carlisle P.; Bessert, Denise A.; Skoff, Robert P.; Hobson, Grace M.
- Abstract
Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating leukodystrophy 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 in the central nervous sytem. Approximately 60% of PMD cases result from genomic 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 with extra copies of Plpl have been developed, none contains an actual genomic rearrangement that resembles those found in PMD patients. We used mutagenic insertion chromosome engineering resources to generate the Plpldup mouse model by introducing an X chromosome duplication in the mouse genome that contains Plpl and five neighboring genes that are also commonly duplicated in PMD patients. The Plpl dup mice display progressive gait abnormalities compared with wild-type littermates. The single duplication leads to increased transcript levels of Plpl and four of the five other duplicated genes over wild-type levels in the brain beginning the second postnatal week. The Pip Jdup mice also display altered transcript levels of other important myelin proteins leading to a progressive degeneration of myelin. Our results show that a single duplication of the Plpl gene leads to a phenotype similar to the pattern seen in human PMD patients with duplications.
- Subjects
PELIZAEUS-merzbacher disease; MYELINATION; LEUKODYSTROPHY; PROTEOLIPIDS; X chromosome; MYELIN
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 29, p11788
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1336-13.2013