N. Carolyn Schanen, M.D., Ph.D.

Adjunct Associate Professor

Head, Human Genetics Research, A.I. duPont Hospital for Children

Phone: (302) 651-6702
Fax: (302) 651-6767
Email: schanen@medsci.udel.edu

Address:
Nemours Biomedical Research
1600 Rockland Road, Room H3B-337
Wilmington, DE 19803

Education

• B.S. - Clemson University
• M.D., Ph.D. - Medical University of South Carolina
• Postdoctoral - Stanford University

Research Interests

The Schanen laboratory is focused on understanding the molecular and cellular basis of human neurogenetic disorders, including Rett syndrome, a form of autism caused by an abnormality of chromosome 15 and an inherited form of stroke. We are also collaborating with Tim Bunnell, Ph.D., to investigate the heritability of speech disorders.

Rett syndrome and chromatin remodeling

Rett syndrome (RTT) is a common cause of mental retardation, affecting approximately 1 in 15,000 females worldwide. These children appear to be normal at birth, then between 6-18 months of age they lose their language, and acquire characteristic hand movements with commensurate loss of purposeful hand skills. A developmental plateau follows the regression, however by that time they are generally nonverbal, often non-ambulatory and appear to be severely mentally retarded. In addition, patients with RTT develop a number of other health problems including osteoporosis, curvature of the spine and epilepsy.

RTT is a genetic disorder that is frequently caused by mutations in the X-linked MECP2 gene. The current model predicts that the MeCP2 protein is a transcriptional silencer that binds methylated CpG residues on DNA and mediates chromatin remodeling by interaction with various other proteins including histone deacetylases, histone methylases and the transcriptional corepressor Sin3A. Cytosine methylation is an important mechanism of gene silencing, both in terms of stable silencing of heterochromatin and in the reversible regulation of gene expression. It is used in processes such as X-chromosome inactivation, imprinting, and the silencing of endogenous retroviruses as well as for tissue specific and developmental regulation of transcription. We are taking several avenues to explore the role of MeCP2 in neuronal and osteoblast function using both cell culture and model organism-based systems.

Autism and chromosome 15 duplications

Autism is a complex group of behavioral disorders associated with deficits in language and social interactions. While most studies agree that autism appears to be largely genetic in origin, the genes that are involved in these disorders remain elusive and standard genome screening strategies have not been fruitful to date. Our group is taking a different tack to understand the basis of autism by studying a chromosome abnormality that is associated with a strong risk of autism. Duplications of the proximal long arm of the maternally derived copy of chromosome 15 are the most common recurrent chromosome abnormality identified in patients with autism spectrum disorders. In addition, duplication chromosome 15 syndrome is associated with varying degrees of cognitive impairment and epilepsy.

The region that is duplicated is subject to gametic imprinting and thus displays parent-of-origin specific gene expression. As part of a NIH-funded program project, we are currently studying the molecular characteristics of chromosome 15 duplications in a large patient cohort to delineate the relationship between these duplications and the clinical presentation. We are using of a combination of standard molecular, cytogenetic and microarray approaches to characterize the duplication regions. While most patients carry similar duplications chromosomes, a subset of patients have been identified with atypical duplications, which will be useful in narrowing in on the genes that contribute to various components of the syndrome.

Notch3 mutations and vascular dementia

The third focus of the laboratory is the relationship between mutations in NOTCH3 and an inherited form of vascular dementia, called CADASIL (an acronym for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The pathologic hallmark of CADASIL is replacement of the vascular smooth muscle cells (VSMC) of small arteries with an amorphous substance. Vessels throughout the body are affected, but symptoms are restricted to the brain where recurrent strokes lead to dementia in mid-adulthood. In arteries, mural VSMC provide tensile strength and contractility. VSMC are not terminally differentiated and can assume a proliferative phenotype associated with decreased expression of contractile proteins. The regulation of phenotypic switching is poorly understood, but the identification of mutations in the NOTCH3 gene in CADASIL has given unexpected insight. Notch coordinates differentiation of adjacent cells along the same pathway and defines borders between cells following different pathways. Our present work is directed toward understanding the functional consequences of CADASIL mutations in well-characterized cell culture systems as well as developing mouse embryonic stem cell and rodent model systems for determining the role of Notch3 in normal VSMC homeostasis.

Current Projects

• Regulation of expression and function of Mecp2 - Studies have shown that the level of expression of MeCP2 is important for neuronal health and function. We are examining the biological mechanisms that are involved in determining the amount of MeCP2 that is produced and how chromatin association of the protein can be modified by extracellular stimuli. Understanding the ways that MeCP2 is regulated may lead to targeted therapies for children with Rett syndrome.
• Identification of downstream transcriptional targets of Mecp2 in the nervous system and bone cells - The ripple effect of loss of a transcriptional regulator is likely to include misexpression of other gene products within the cell that can affect cell function. We are using a variety of experimental approaches to identify genes that are directly regulated by Mecp2 in both neuronal and bone cells.
• Characterization of duplications of chromosome 15q11q13 and their association with autism - We are examining the chromosomal duplications found in a large cohort of patients to determine whether structural features of the duplications are important in determining the severity of the symptoms and the presence or absence of specific symptoms.
• Genetics of speech disorders - In collaboration with Tim Bunnell, Ph.D. (Nemours Biomedical Research), we are examining the heritability of speech traits in a group of sibling pairs including one child with an articulation disorder.
• Understanding the role of Notch3 signaling in vascular smooth muscle cells - The stereotyped mutations in the Notch3 protein lead to attrition of VSMC in the vessel. We are focusing on the role that Notch3 plays in regulating differentiation of VSMC and examining the impact of the mutations on the ability of the cells to respond appropriately to extracellular cues.

Research Group

• Keping Hu, Ph.D. - Research Associate (Ph.D., Research Institute of Pharmaceutical Chemistry Beijing, China). Role of posttranslational modification in Mecp2 function.
• Asmita Kumar, Ph.D. - Postdoctoral Fellow (Ph.D., University of Mississippi). Characterization of chromatin association of Mecp2 using live cell imaging.
• Alex Parokonny, Ph.D. - Research Associate (Ph.D., National Academy of Sciences, Ukraine). Cytogenetic analyses of chromosome 15 duplications.
• Andrea Ham, M.S. - Graduate Student (M.S., The American University). Regulation of Mecp2 expression in neurons by extracellular stimuli.
• Rose Deeter, B.S. - Graduate Student (B.S., Lehigh University). Regulation of gene expression by Mecp2 in osteoblasts.
• Joanna Dragich, B.A. - UCLA Graduate Student (B.S., Carnegie Mellon University). Characterization of Mecp2 transcription in the postnatal mouse brain. Examining the effects of loss of Mecp2 on gene expression in Mecp2 null mice.
• Jennette Driscoll, B.S. - Research Assistant (B.A., University of Delaware). Heritability of speech traits and articulation disorders. Molecular analysis of chromosome 15q duplications.
• Marvin Kendall, B.S. - Research Associate (B.S., University of Delaware). Role of Notch3 in regulation of VSMC differentiation.
• Barb Malone, B.S. - Senior Research Assistant (B.S., University of Delaware). Identification of Mecp2 transcriptional targets in neurons.

Selected Publications

• Hogart A, Leung KN, Wang NJ, et al. Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet. 2009;46(2):86–93.
• Hogart A, Wu D, Lasalle JM, Schanen NC. The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13. Neurobiol Dis. 2009:in press.
• Tao J, Hu K, Chang Q, et al. Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc Natl Acad Sci U S A. 2009;106(12):4882–4887.
• Kumar A, Kamboj S, Malone BM, et al. Analysis of protein domains and Rett syndrome mutations indicate that multiple regions influence chromatin-binding dynamics of the chromatin-associated protein MECP2 in vivo. J Cell Sci. 2008;121(Pt 7):1128–1137.
• Wang NJ, Parokonny AS, Thatcher KN, et al. Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15. BMC Genet. 2008;9:2.
• Dragich JM, Kim Y-H, Arnold AP, Schanen NC. Differential distribution of the MeCP2 splice variants in the postnatal mouse brain. J Comp Neurol. 2007;501(4):526–542.
• Nishimura Y, Martin CL, Vazquez-Lopez A, et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet. 2007;16(14):1682–1698.
• Parokonny AS, Wang NJ, Driscoll J, et al. Atypical breakpoints generating mosaic interstitial duplication and triplication of chromosome 15q11-q13. Am J Med Genet A. 2007;143a(20):2473–2477.
• Chang JH, Vuppalanchi D, van Niekerk E, Trepel JB, Schanen NC, Twiss JL. PC12 cells regulate inducible cyclic AMP (cAMP) element repressor expression to differentially control cAMP response element-dependent transcription in response to nerve growth factor and cAMP. J Neurochem. 2006;99(6):1517–1530.
• Schanen NC. Epigenetics of autism spectrum disorders. Hum Mol Genet. 2006;15 Spec No 2:R138–50.
• Twiss JL, Chang JH, Schanen NC. Pathophysiological mechanisms for actions of the neurotrophins. Brain Pathol. 2006;16(4):320–332.
• Ham AL, Kumar A, Deeter R, Schanen NC. Does genotype predict phenotype in Rett syndrome? J Child Neurol. 2005;20(9):768–778.
• Haritunians T, Chow T, De Lange RPJ, et al. Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry. 2005;76(9):1242–1248.
• Mann SM, Wang NJ, Liu DH, et al. Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy. Hum Genet. 2004;115(2):104–111.
• Mnatzakanian GN, Lohi H, Munteanu I, et al. A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat Genet. 2004;36(4):339–341.
• Schanen C, Houwink EJF, Dorrani N, et al. Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome. Am J Med Genet A. 2004;126a(2):129–140.
• Wang NJ, Liu D, Parokonny AS, Schanen NC. High-resolution molecular characterization of 15q11-q13 rearrangements by array comparative genomic hybridization (array CGH) with detection of gene dosage. Am J Hum Genet. 2004;75(2):267–281.
• Agate RJ, Grisham W, Wade J, et al. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. Proc Natl Acad Sci U S A. 2003;100(8):4873–4878.
• Chang JH, Mellon E, Schanen NC, Twiss JL. Persistent TrkA activity is necessary to maintain transcription in neuronally differentiated PC12 cells. J Biol Chem. 2003;278(44):42877–42885.
• Hammer S, Dorrani N, Hartiala J, Stein S, Schanen NC. Rett syndrome in a 47,XXX patient with a de novo MECP2 mutation. Am J Med Genet A. 2003;122a(3):223–226.
• Kudo S, Nomura Y, Segawa M, et al. Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain. J Med Genet. 2003;40(7):487–493.
• Haritunians T, Boulter J, Hicks C, et al. CADASIL Notch3 mutant proteins localize to the cell surface and bind ligand. Circ Res. 2002;90(5):506–508.
• Kudo S, Nomura Y, Segawa M, et al. Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation. J Med Genet. 2002;39(2):132–136.
• Kudo S, Nomura Y, Segawa M, et al. Functional analyses of MeCP2 mutations associated with Rett syndrome using transient expression systems. Brain Dev. 2001;23 Suppl 1:S165–73.
• Leonard H, Silberstein J, Falk R, et al. Occurrence of Rett syndrome in boys. J Child Neurol. 2001;16(5):333–338.

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