Grace M. Hobson, Ph.D.

Adjunct Associate Professor

Senior Research Scientist and Lab Head, Neurogenetics Research Laboratory, A.I. duPont Hospital for Children

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

Address:
Alfred I. duPont Hospital for Children
Nemours Biomedical Research A/R 285
1600 Rockland Road
Wilmington, DE 19803

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), X-linked disorders of myelin formation in the central nervous system. These diseases are caused by several kinds of mutations of the gene for the most abundant protein of myelin, the proteolipid protein 1 gene (PLP1). 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.

In the Neurogenetics Research Laboratory, we are examining the molecular mechanisms involved in two kinds of genetic defects: (1) mutations that may cause alterations in splicing and (2) genomic rearrangements in and around the PLP1 locus, the most common of which is duplication. 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 PLP1 and its expression has broad implications for other dysmyelinating and demyelinating diseases such as cerebral palsy and multiple sclerosis.

Current Projects

• Regulation of PLP1 splicing - Most known disease-causing mutations of PLP1 are located in exons and affect the amino acid sequence of the PLP1 protein, but we have found that about 20% of PLP1 mutations, some of which are in introns, cause disease by affecting splicing of PLP1. 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. Understanding how PLP1 splicing is regulated may lead to therapeutic approaches for some patients with PMD.
• Characterization of duplications and correlation with disease phenotype - Supported by a grant from the NIH, we are investigating the molecular characteristics of duplications and other copy number variability in and around the PLP1 locus in a large cohort of patients using quantitative PCR, array comparative genomic hybridization (aCGH), and fluorescent in situ hybridization (FISH). These characteristics include the size and orientation of the duplication, the location of the endpoints, and the sequence at abnormal junctions formed by the rearrangements. These studies will help us understand the mechanisms whereby duplications are generated. We are also working with Dr. James Garbern, Wayne State University, to discover how our molecular findings correlate with the clinical characteristics of our patients.
• Analysis of a mouse model of PMD due to duplication of PLP1 - We have generated a mouse model of the PMD duplication. The duplication in this model is similar to those in human PMD patients in size and includes other genes in the vicinity of PLP1, as do human duplications. Supported by a grant from the NIH, we are using our model to determine how duplication leads to disruption of the myelin program in males and compensatory skewing of the X-chromosome inactivation pattern in females.
• Molecular diagnostics development - Another research interest is to improve the molecular diagnostics of PMD/SPG2 by refining molecular techniques and adding new tests. An estimated 5 to 20% of patients with clinical findings consistent with PMD do not have a duplication or a mutation in of PLP1, so we are also identifying other disease-causing loci and setting up new diagnostic tests.

Research Group

• Karen Sperle, M.S. - Research Associate (M.S., Hood College).
• Angelique Davis-Williams, M.S. - Research Assistant (M.S., University of Medicine and Dentistry of New Jersey).
• Linda Banser, B.A. - Research Assistant (B.A., Lehman College).
• Kristi Clark, B.S. - Graduate Student (B.S., Cedar Crest College), University of Delaware.
• Heather Keskeny - Volunteer.
• Danielle Lavoie - Undergraduate Student, University of Delaware.

Selected Publications

• Fattal-Valevski A, Dimaio MS, Hisama FM, et al. Variable Expression of a Novel PLP1 Mutation in Members of a Family With Pelizaeus-Merzbacher Disease. J Child Neurol. 2009:in press.
• Wang E, Dimova N, Sperle K, et al. Deletion of a splicing enhancer disrupts PLP1/DM20 ratio and myelin stability. Exp Neurol. 2008;214(2):322–330.
• Gorman MP, Golomb MR, Walsh LE, et al. Steroid-responsive neurologic relapses in a child with a proteolipid protein-1 mutation. Neurology. 2007;68(16):1305–1307.
• Hobson GM, Huang Z, Sperle K, et al. Splice-site contribution in alternative splicing of PLP1 and DM20: molecular studies in oligodendrocytes. Hum Mutat. 2006;27(1):69–77.
• Lee JA, Madrid RE, Sperle K, et al. Spastic paraplegia type 2 associated with axonal neuropathy and apparent PLP1 position effect. Ann Neurol. 2006;59(2):398–403.
• Wang E, Huang Z, Hobson GM, et al. PLP1 alternative splicing in differentiating oligodendrocytes: characterization of an exonic splicing enhancer. J Cell Biochem. 2006;97(5):999–1016.
• Wolf NI, Sistermans EA, Cundall M, et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease. Brain. 2005;128(Pt 4):743–751.
• Woodward KJ, Cundall M, Sperle K, et al. Heterogeneous duplications in patients with Pelizaeus-Merzbacher disease suggest a mechanism of coupled homologous and nonhomologous recombination. Am J Hum Genet. 2005;77(6):966–987.
• Garbern JY, Krajewski K, Hobson G. PLP1-Related Disorders. In: GeneReviews at GeneTests: Medical Genetics Information Resource. University of Washington, Seattle; 2004.
• Lee ES, Moon HK, Park YH, Garbern J, Hobson GM. A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. J Neurol Sci. 2004;224(1-2):83–87.
• Shy ME, Hobson G, Jain M, et al. Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy. Ann Neurol. 2003;53(3):354–365.
• Garbern J, Hobson G. Prenatal diagnosis of Pelizaeus-Merzbacher disease. Prenat Diagn. 2002;22(11):1033–1035.
• Hobson GM, Huang Z, Sperle K, Stabley DL, Marks HG, Cambi F. A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann Neurol. 2002;52(4):477–488.
• Starling A, Rocco P, Cambi F, Hobson GM, Passos Bueno MR, Zatz M. Further evidence for a fourth gene causing X-linked pure spastic paraplegia. Am J Med Genet. 2002;111(2):152–156.
• Hobson G, Stabley D, Funanage V, 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. 2001;17(2):152.
• Hobson GM, Davis AP, Stowell NC, et al. Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease. Neurology. 2000;55(8):1089–1096.
• Hobson GM, Funanage VL, Elsemore J, et al. Developmental expression of creatine kinase isoenzymes in chicken growth cartilage. J Bone Miner Res. 1999;14(5):747–756.
• Stanton RP, Hobson GM, Montgomery BE, Moses PA, Smith-Kirwin SM, Funanage VL. Glucocorticoids decrease interleukin-6 levels and induce mineralization of cultured osteogenic cells from children with fibrous dysplasia. J Bone Miner Res. 1999;14(7):1104–1114.
• Bachinski LL, Abchee A, Durand JB, Roberts R, Krahe R, Hobson GM. Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies. Mol Cell Probes. 1997;11(1):55–58.
• Koty PP, Pegoraro E, Hobson G, et al. Myotonia and the muscle chloride channel: dominant mutations show variable penetrance and founder effect. Neurology. 1996;47(4):963–968.
• Hobson GM, Krahe R, Garcia E, Siciliano MJ, Funanage VL. 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. 1995;29(3):704–711.
• Mitchell MT, Hobson GM, Benfield PA. TATA box-mediated polymerase III transcription in vitro. J Biol Chem. 1992;267(3):1995–2005.
• Hobson GM, Molloy GR, Benfield PA. Identification of cis-acting regulatory elements in the promoter region of the rat brain creatine kinase gene. Mol Cell Biol. 1990;10(12):6533–6543.
• Horlick RA, Hobson GM, Patterson JH, Mitchell MT, Benfield PA. Brain and muscle creatine kinase genes contain common TA-rich recognition protein-binding regulatory elements. Mol Cell Biol. 1990;10(9):4826–4836.
• Benfield PA, Graf D, Korolkoff PN, Hobson G, Pearson ML. Isolation of four rat creatine kinase genes and identification of multiple potential promoter sequences within the rat brain creatine kinase promoter region. Gene. 1988;63(2):227–243.

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