Grace M. Hobson, Ph.D.

Research Scientist, Musculoskeletal Inherited Diseases Laboratory

Contact

Hobson

Alfred I. duPont Hospital for Children
Research Department
P.O. Box 269
Wilmington, DE 19899

Phone: (302) 651-6829
Fax: (302) 651-6899
E-mail: ghobson@nemours.org

Education

B.S.: Mary Washington College of the University of Virginia
M.Ed.: University of Virginia
Ph.D.: University of Delaware

Research Interests

Our work is focused on understanding the molecular mechanisms underlying the pathogenesis of human neurodegenerative disease. A primary focus is on Pelizaeus-Merzbacher Disease (PMD) and Spastic Paraplegia 2 (SPG2). These are disorders of central nervous system myelin formation caused by duplication or mutation of the gene for the most abundant protein of myelin, the proteolipid protein (PLP) gene. PMD and SPG2 actually represent a spectrum of disease severities from mild SPG2, which is characterized by hypomyelination and spastic paraparesis, to severe forms of PMD, characterized by almost complete absence of white matter and severe quadriparesis. Other classic symptoms of PMD include nystagmus, hypotonia, cognitive impairment, head titubations, and ataxia. Since PMD/SPG2 is an X-linked recessive disorder, it predominantly affects males, but female carriers may manifest symptoms of the disease, usually in its milder forms. Most known disease-causing mutations of the PLP gene are located in exons, but we and others have identified mutations in introns that cause disease by affecting splicing of the PLP gene. Of particular interest to us are mutations that differentially affect the amounts of alternatively spliced mRNA products of the gene. We are using a cell culture system and a transgenic mouse model to study the effects of these mutations. Further, we are investigating the molecular characteristics of duplications of the PLP gene that cause PMD, including the size and orientation of the duplication and the location of the breakpoints to elucidate the mechanisms whereby duplications are generated. We work closely with our clinical collaborators, Dr. Franca Cambi at the University of Kentucky and Drs. John Kamholz, James Garbern, Michael Shy, and Alex Gow 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 and identifying other disease-causing loci. 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. 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.

The results of our studies will allow improved clinical and molecular diagnosis and genetic counseling, which should 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.

Current Projects

• Investigation of the molecular basis for the spectrum of disease severities caused by mutations of the PLP gene.
• Examination of the size, orientation, and breakpoints of duplications that cause PMD.
• Identification and characterization of splicing enhancer elements that regulate PLP/DM20 alternative splicing.

Research Group

• Karen Sperle, M.S. - Research Assistant (M.S., Hood College).
• Angelique Davis, M.S. - Research Assistant (M.S., University of Medicine and Dentistry of New Jersey) Molecular diagnostics.

Selected Publications

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., in press.

Garbern, J., Krajewski, K., and Hobson, G. (updated June 2004) PLP1-Related Disorders in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2004.

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.

Garbern, J. and Hobson, G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat. Diagn. 22:1033-1035, 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.

Starling, A., Rocco, P., Calmbi, F., Hobson, G.M., Passos Bueno, M.R., and Zatz, M. Further evidence for a fourth gene causing X-linked pure spastic paraplegia. Am. J. Med. Genet., submitted.

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.

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.

Stanton, R.P., Hobson, G.M., Montgomery, B.E., Moses, P.A., Smith-Kirwin, S.M., and Funanage, V.L. Glucocorticoids decrease interleukin-6 levels and induce mineralization of cultured osteogenic cells from children with fibrous dysplasia. J. Bone and Miner. Res. 14:1104-1114, 1999.

Hobson, G.M., Funanage, V.L., Elsemore, J., Yagami, M., Rajpurohit, R., Perriard, J-C., Hickok, N.J., Shapiro, I.M., and Tuan, R.S. Developmental expression of creatine kinase isoenzymes in chicken growth cartilage. J. Bone Miner. Res. 14:747-756, 1999.

Bachinski, L.L., Abchee, A., Durand, J.-B., Roberts, R., Krahe, R., and Hobson, G.M. Trinucleotide repeat polymorphism in the human MADS Domain Transcription Enhancer Factor 2A (MEF2A) gene at 15q26 is not expanded in cardiomyopathy. Mol. Cell. Probes 11:55-58, 1997.

Koty, P.P., Pegoraro, E., Hobson, G.M., Marks, et al. Myotonia and the muscle chloride channel: Dominant mutations show variable penetrance and founder effect. Neurology 47:963-968, 1996.

Hobson, G.M., Krahe, R., Garcia, E., Siciliano, M.J., and Funanage, V.L. Regional chromosomal assignments for four members of the MADS Domain Transcription Enhancer Factor 2 (MEF2) gene family to human chromosomes 15q26, 19p12, 5q14, and 1q12-q23. Genomics 29:704-711, 1995.

Mitchell, M.T., Hobson, G.M., and Benfield, P.A. TATA box mediated polymerase III transcription in vitro. J. Biol. Chem. 267:1995-2005, 1992.

Hobson, G.M., Molloy, G.R., and Benfield, P.A. Identification of cis-acting regulatory elements in the promoter region of the rat brain creatine kinase gene. Mol. Cell. Biol. 10:6533-6543, 1990.

Horlick, R.A., Hobson, G.M., Mitchell, M.T., Molloy, G.R., and Benfield, P.A. Brain and muscle creatine kinase genes contain common TA-rich recognition protein-binding regulatory elements. Mol. Cell. Biol. 10: 4826-4836, 1990.

Hobson, G.M., Mitchell, M.T., Molloy, G.R., Pearson, M.L., and Benfield, P.A. Identification of a novel TA-rich DNA binding protein that recognizes a TATA sequence within the brain creatine kinase promoter. Nuc. Acids. Res. 16:8925-8944, 1988.

Benfield, P.A., Graf, D., Korolkoff, P., Hobson, G., and Pearson, M.L. Isolation of four rat creatine kinase genes and identification of multiple potential promoter sequences within the rat brain creatine kinase promoter region. Gene 63:227-243, 1988.