Molecular Mechanisms of Pelizaeus-Merzbacher Disease
Target Investigator:
Grace M Hobson, MEd, PhD
Head – Neurogenetics Research Laboratory
Collaborators: Dr. James Garbern, M.D., Ph.D., Wayne State University
Mentors: John Kamholz, M.D., Ph.D., Wayne State University
N. Carolyn Schanen, M.D., Ph.D., Nemours Biomedical Research


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. Patients with PMD have dysmyelination or demyelination and symptoms include spastic paraparesis, nystagmus, hypotonia, cognitive impairment, head titubations, and ataxia.

We are examining the underlying molecular genetic consequences of two kinds of mutations that cause PMD: mutations that may cause alterations in RNA splicing and gene duplications in and around the PLP1 locus that may alter PLP1 expression. In one project, we are investigating the mechanism by which two alternative forms of PLP1 are made and how patient mutations interfere with the process. For these studies, we use a minigene construct in a cell culture system to examine the effects of mutations on alternative splicing and to determine how the binding of protein factors is affected by the mutations. In another project, we are determining the molecular mechanisms that cause the most common type of PMD, gene duplication at the PLP1 locus. For these studies, we are examining the duplications in a cohort of patients for clues as to how they were formed using a combination of strategies, including fluorescent in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and junction analysis. In another project, we are generating a mouse model with a duplication that is similar to the duplications in most PMD patients. We will use the model to analyze how tandem gene duplication can alter the myelin program in males and the X-chromosome inactivation pattern in females.


Figure 1. Fluorescent in situ hybridization (FISH) showing a duplication of PLP1 in a male patient. Labeled cosmid probes for PLP1 and androgen receptor (AR) were hybridized to nuclei of white blood cells. Both PLP1 and AR are located on the X chromosome. The duplication is indicated by two PLP1 signals compared with one AR signal in the nucleus of a cell.


Figure 2. Array comparative genomic hybridization (aCHG) showing the extent of duplication in a male patient. Labeled DNA of a patient was hybridized against control DNA to arrayed oligonucleotides specific for regions along the X chromosome. Results are expressed as log2 of fluorescence ratios. The duplicated region on the X chromosome can be seen as a region of elevated signals.

Related Publications:

    Hobson, G.M., Davis, A.P., Stowell, N.C., Kolodny, E.H., Sistermans, E.A., de Coo, I.M.F., Funanage, V.L., and Marks, H.G. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology, 55(8):1089-1096, 2000.
    Hobson, G., Stabley, D., Funanage, V., and Marks, H. A new polymorphism in the proteolipid protein (PLP1) gene and its use for carrier detection of PLP1 gene duplication in Pelizaeus-Merzbacher disease. Hum Mutat (2):152, 2001.
    Starling, A., Rocco, P., Cambi, F., Hobson, G., Passos Bueno, M.R., and Zatz, M. Further evidence for a fourth gene causing X-linked pure spastic paraplegia. Am. J. Med. Genet., 111:152-156, 2002.
    Hobson, G.M., Huang, Z., Sperle, K., Stabley, D.L., Marks, H.G., and Cambi, F. A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann. Neurol. 52:477-488, 2002.
    Garbern, J. and Hobson, G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat. Diagn. 22:1033-1035, 2002.
    Shy, M.E., Hobson, G.M., Jain, M., Boespflug-Tanguy, O., Garbern, J.Y., Sperle, K., Li, W., Gow, A., Rodriguez, D., Bertini, E., Mancias, P., Krajewski, K., Lewis, R., Kamholz, J. Schwann Cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann. Neurol. 53:354-365, 2003.
    Lee, E.S., Moon, H.K., Park, Y.H., Garbern, J., and Hobson, G.M. A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. J Neurol Sci 224:83-87, 2004.
    Wolf, N.I., Sistermans, E.A., Cundall, M., Hobson, G.M., Davis-Williams, A.P., Palmer, R., Stubbs, P., Davies, S., Endziniene, M., Wu, Y., Chong, W.K., Malcolm, S., Surtees, R., Garbern, J.Y., and Woodward, K. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain 128:743-751, 2005.
    Woodward, K.J., Cundall, M., Sperle, K., Sistermans, E.A., Ross, M., Howell, G., Gribble, S.M., Burford, D.C., Carter, N.P., Hobson, D.L., Garbern, J.Y., Kamholz, J., Heng, H., Hodes, M.E., Malcolm, S., and Hobson, G.M. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet 77:966-987, 2005.
    Hobson, G.M., Huang, Z., Sperle, K., Sistermans, E., Rogan, P.K., Garbern, J.Y., Kolodny, E., Naidu, S., and Cambi, F. Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Hum Mutat 27:69-77, 2006.
    Wang, E., Huang, Z., Hobson, G.M., Dimova, N., Sperle, K., McCullough, A., and Cambi, F. PLP1 alternative splicing in differentiating oligodendrocytes: characterization of an exonic splicing enhancer. J Cell Biochem 97:999-1016, 2006.
    Lee, J.A., Madrid, R.E., Sperle, K., Ritterson, C.M., Hobson, G.M., Garbern, J., Lupski, J.R., and Inoue, K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol 59:398-403, 2006.
    Garbern, J., Krajewski, K., Hobson, G. (updated September 2006) PLP1-Related Disorders in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2006.
    Gorman, M.P., Golomb, M.R., Walsh, L.E., Hobson, G.M., Garbern, J.Y., Kinkel, B.T., Darras, B.T., Urion, D.K. Eksioglu, Y.Z. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology 68:1305-1307, 2007.