Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by genetic defects of the proteolipid protein 1 gene (PLP1) that encodes the major central nervous system myelin protein. Duplication of a gene region containing PLP1 is the most common cause of PMD, accounting for over 60% of cases. Although there can be variability in the severity of the disease, even within a single family, most patients with PLP1 duplications have a similar phenotype with onset of nystagmus and hypotonia in the first months of life, and limb and gait ataxia, spastic quadriparesis, and cognitive and visual impairment during the first decade. Motor milestones and speech are also delayed in most patients. Neither the molecular mechanisms of gene duplication nor the molecular basis for the clinical phenotype in PMD is well understood. In our previous studies of the DNA sequences of recombinant junctions in 13 patients with PMD, we have found data consistent with a coupled homologous, nonhomologous recombination mechanism causing the gene duplications. Lupski and co-workers, however, recently suggested from the analysis of recombinant junctions in 2 patients with complex rearrangements that a replication-based mechanism may also be involved in this process. In the proposed studies, we will analyze the structure and sequence of the recombination breakpoints in a larger cohort of patients with gene duplications using a combination of strategies, including high-density oligonucleotide arrays. In addition, to further understand the basis of the clinical phenotype caused by these complex gene duplications, we will construct a mouse model of PMD containing a large, complex duplication of the PLP1 region of the X-chromosome. ES cells containing this duplication have been constructed, and mice containing the rearranged portion of the X-chromosome are being made. Animals will then be analyzed for their clinical phenotype, the expression of genes encoded by the duplication, including PLP1, as well as expression of other genes in the program of myelination. Segregation of the rearranged portion of the X- chromosome will also be examined in female carriers for its effects on X-inactivation. Taken together, these studies will provide important new information on the mechanism of gene duplication in PMD, as well as the effect of this gene duplication on gene expression and neurological function. Our group is particularly well poised to perform these studies because of the unique patient resource we have developed and the expertise we have gained from a commitment to PMD diagnostics and research during the past decade.
The specific aims are: (1) To test the hypothesis that genomic rearrangements in PMD patients frequently occur as complex rearrangements, including a second duplicated region and deleted, triplicated or inverted regions, consistent with a coupled homologous, nonhomologous recombination mechanism. (2) To test the hypothesis that the presence of a gene duplication at the Plp1 locus alters Plp1 gene expression leading to disruption of the myelin program in males and compensatory skewing of the X-chromosome inactivation pattern in females.

Public Health Relevance

This research is directly relevant to public health because it will lead to a better understanding of genetic disease mechanisms, which will ultimately improve diagnostic and therapeutic approaches for PMD and other disorders that result from complex genomic and genetic mutational events.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS058978-01A2S1
Application #
7913108
Study Section
Special Emphasis Panel (ZRG1-MNG-B (01))
Program Officer
Tagle, Danilo A
Project Start
2009-01-15
Project End
2009-12-31
Budget Start
2009-09-01
Budget End
2009-12-31
Support Year
1
Fiscal Year
2009
Total Cost
$39,750
Indirect Cost
Name
Alfred I. Du Pont Hosp for Children
Department
Type
DUNS #
038004941
City
Wilmington
State
DE
Country
United States
Zip Code
19803
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Nevin, Zachary S; Factor, Daniel C; Karl, Robert T et al. (2017) Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes. Am J Hum Genet 100:617-634
Rodriguez, Elena; Sakowski, Lauren; Hobson, Grace M et al. (2015) Plp1 gene duplication inhibits airway responsiveness and induces lung inflammation. Pulm Pharmacol Ther 30:22-31
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Taube, Jennifer R; Sperle, Karen; Banser, Linda et al. (2014) PMD patient mutations reveal a long-distance intronic interaction that regulates PLP1/DM20 alternative splicing. Hum Mol Genet 23:5464-78
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Sima, Anders A F; Pierson, Christopher R; Woltjer, Randall L et al. (2009) Neuronal loss in Pelizaeus-Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol 118:531-9