Neurogenetics Research Lab

Grace M. Hobson, Ph.D. Laboratory Head

Major Research Interests

Our work is focused on understanding molecular mechanisms underlying the pathogenesis of human neurodegenerative disease. The primary focus is on Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia 2 (SPG2). These diseases are X-linked leukodystrophies caused by genetic defects of the proteolipid proein 1 gene (PLP1) that encodes the major central nervous system myelin protein. The clinical phenotype of PMD ranges from a mild muscle tightness in some patients to severe early onset motor weakness and delay in congnitive development in others. Interestingly, there is also a varied and complex set of PLP1 mutations, including gene duplications, coding sequence mutations and splicing mutations that are associated with the these clinical phenotypes, although how each of these mutations causes disease is not well understood. We are examining the underlying molecular genetic consequences of two kinds of PMD mutations: mutations that may cause alterations in alternative splicing and gene duplications in and around the PLP1locus that may alter PLP1 expression.We also work with our clinical collaborators Dr. Franca Cambi at the University of Kentucky and Dr. John Kamholz and James Garbern at Wayne State University to discover how our molecular findings correlate with the clinical characteristics of our patients.

Another research interest is to improve the molecular diagnostics of PMD/SPG2 by refining molecular techniques. Currently, the Molecular Diagnostics Laboratory at the Alfred I. duPont Hospital for Children is one of a few laboratories in the world offering clinical molecular diagnostics for both duplication and mutation of the PLP gene.

The results of our studies will allow improved clinical and molecular diagnosis and genetic counseling, which will help decrease the incidence of these devastating diseases. We will gain insights into the mechanisms of the disease processes, thereby aiding in the development of effective strategies for therapy. In addition, what we learn about the PLP gene and its expression has broad implications for other dysmyelinating and demyelinating diseases.

For further information, please visit the PMD Foundation (www.pmdfoundation.org).

Dr. Hobson is Director of Molecular Diagnostics for Pelizaeus-Merzbacher disease, a genetic disease of the central nervous system. The diagnostics laboratory is the only one in the USA and one of two in the world offering molecular diagnostics for both mutation and duplication of the gene that causes this devastating disease. One of our research interests is to improve the molecular diagnostics of PMD by refining the molecular techniques. Other research projects are focused on understanding the molecular mechanisms underlying the pathogenesis of PMD.

As Radiation Safety Officer, Dr. Hobson is responsible for administering the radiation safety program for Nemours Biomedical Research and assuring adherence to federal, state, and local regulations regarding use of radioactive materials.

Current Projects

• Gene duplication and Pelizaeus-Merzbacher disease
• Splicing and genetic disease

Current Research Group

• Grace M. Hobson, PhD - Dr. Hobson is Head of the Neurogenetics Research Laboratory, Director of Diagnostics for Pelizaeus-Merzbacher disease, and Radiation Safety Officer.
• Jennifer Remington Taube, PhD - Dr. Taube is a Postdoctoral Fellow working on the alternative splicing project.
• Karen Sperle, MS - Karen is a Research Assistant working on the gene duplication project. Angelique P., MS - Angelique Davis-Williams primary focus is DNA diagnostics of Pelizaeus-Merzbacher disease (PMD). PMD is an X-linked disorder affecting myelin formation in the central nervous system. Our Molecular Diagnostics Laboratory offers clinical molecular diagnostics for both duplication and mutation of the PLP gene. An estimated 5% to 20% of patients with clinical findings consistent with PMD do not have a duplication or a mutation in an exon or intron-exon junction of the PLP gene.
• Linda Banser, BA - Linda is a Research Assistant working on the gene duplication project. She also assists with DNA diagnostics of PMD and PMLD.

Recent Publications

1. 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, 55:1089-1096, 2000. Selected for Continuing Medical Education (CME) and for editorial comment: Percy, A.K. Pelizaeus-Merzbacher disease: Splice sites are nice sites for disease expression. Neurology, 55:1072-1073, 2000.
2. 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 17:152, 2001.
3. 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.
4. 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.
5. Garbern, J. and Hobson, G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat. Diagn. 22:1033-1035, 2002.
6. Shy, M.E., Hobson, G., Jain, M., Boespflug-Tanguy, O., Garbern, J., Sperle, K., Li,W., Gow, A., Rodriguez, D., Bertini, E., Mancias, P., Krajewski, K., Lewis, R., and Kamholz, J. Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann. Neurol. 53:354-65, 2003.
7. 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.
8. 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.
9. 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., Hobson, G.M. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and non-homologous recombination. Am J Hum Genet 77:966-987, 2005.
10. Hobson, G.M., Huang, Z., Sperle, K., Sistermans, E., Rogan, P.K., Garbern, J.Y., Kolodny, E., Naidu, S., Cambi, F. Splice site contribution in alternative splicing of PLP1 and DM20: Molecular studies in oligodendrocytes. Hum Mutat 27:69-77, 2006.
11. Lee, J.A., Madrid, R.E., Sperle, K., Ritterson, C.M., Hobson, G.M., Garbern, J., Lupski, J.R., Inoue, K. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol 59:398-403, 2006.
12. Wang, E., Huang, Z., Hobson, G.M., Dimova, N., Sperle, K., McCullough, A., Cambi, F. PLP1 alternative splicing in differentiating oligodendrocytes: Characterization of an exonic splicing enhancer. J Cell Biochem 97:999-1016, 2006.
13. Garbern, J., Krajewski, K., and Hobson, G. (last updated September 2006) PLP1-Related Disorders in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2004. Available at http://www.genetests.org/.
14. 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.