Back to Search Results
M. Chiara Manzini
Adjunct Assistant Professor of Pharmacology and Physiology
Office Phone: 202-994-3541
Department: Pharmacology and Physiology
- B.S., University of Pavia, Italy, 1998
- M.A., Columbia University, 1999
- PhD, Columbia University, 2006
MolMed 8280: Molecular Pharmacology and Neurobiology of Excitable Tissues
MolMed 8282: Neural Development and Neurodevelopmental Disorders
Normal neuronal differentiation and circuit formation in the brain are necessary for the development of cognitive function and are often disrupted in neurodevelopmental disorders such an intellectual disability and autism. My research goal has been to understand the cellular and molecular mechanisms of human disorders that affect neuronal differentiation by identifying causative genetic mutations and developing appropriate animal models of disease in both mouse and zebrafish. My long-term research goal is to study the genetics and biology of cognitive disorders exploring the mechanisms of extracellular interactions and intracellular signaling.
Main research projects
The role of the extracellular matrix in brain development
The extracellular matrix (ECM) is a meshwork of proteins and polysaccharides residing in close opposition to the cell membrane. Originally thought to play a simple structural role, the ECM is emerging as an important regulator of diverse aspects of cellular differentiation, from proliferation to cell death. Mutations in genes encoding ECM components such as laminins and collagens as well as cellular ECM receptors and enzymes involved in ECM receptor glycosylation cause a spectrum of severe brain malformations which are often found in combination with muscular dystrophy. These findings suggest that these ECM genes must act together or in parallel pathways to control brain development, but the exact mechanisms are unknown. The work in my lab focuses on the identification of novel disease genes in families affected by the disorders of cell-ECM interaction and then replicates the disease in animal models (zebrafish and mouse) with the dual goal to 1) study the mechanisms underlying disease and 2) explore the biological function of the disease genes to better understand normal brain development.
Intracellular signaling in intellectual disability and autism spectrum disorder
Intellectual disability (ID) and autism spectrum disorder (ASD) affect 2-3% of the US population and are is caused by a vast array of genetic mutations. By identifying the genes involved in ASD/ID, we can begin to make sense of this extreme heterogeneity and determine whether common signaling pathways are involved, and whether patients can be classified according to gene function. During my postdoc I studied families affected by different forms of ASD and ID and identified novel loss-of-function mutations in two genes for which only one allele was previously known. One mutation in the endosomal trafficking gene SPG20 causes Troyer syndrome, a form of spastic paraplegia associated with ID. The second mutation affects the CC2D1A gene and is responsible for a severe non-syndromic form of ID. As SPG20, Cc2d1a is also involved in endo-lysosomal trafficking of various transmembrane receptors and in the regulation of receptor signaling to the nucleus. Endosomal trafficking of internalized receptors is an important regulator of cellular responses to extracellular signaling cues, and it is still poorly understood in the nervous system. There is a growing group of neurodevelopmental disease genes involved in endosomal trafficking, suggesting a mechanism, which may be common to patients with different genetic causes. We are currently developing animal models and using a combination of cell biology, biochemistry and behavioral assays to study the role of ID genes in the development of cognition.
Please visit our website: http://www.manzinilab.org/
View publications by this faculty member.
Stevens E., Carss K., Cirak S., Foley A.R., Torelli S., Willer T., Tambunan D.E., Yau S., Brodd L., Sewry C., Feng L., Haliloglu K., Orhan D., Dobyns W.B., Enns G.M., Manning M., Krause A., Salih M.A., Walsh C.A., Hurles M., Campbell K.C., Manzini M.C., UK10K Consortium, Stemple D., Lin Y-Y., Muntoni F. Mutations in B3GALNT2 cause congenital muscular dystrophy with hypoglycosylation of alpha-dystroglycan. Am J Hum Genet 92(3):354-365 (2013)
Manzini M.C., Tambunan D.E., Hill R.S., Yu T.W., Heinzen E.L., Shianna K.V., Partlow J.N., Barry B.J., Rodriguez J., Gupta V.A., Beggs A.H., AlQudah A-K, Eyaid W.M., Friedman J.M., Salih M.A., Clark R., Mora M., Moroni I., Walsh C.A. Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause for Walker Warburg Syndrome. Am J Hum Genet 91(3):541-7 (2012)
Gupta V.A., Kawahara G., Myers J.A., Chen A.T., Hall T.E., Manzini M.C., Currie P.D., Zhou Y., Zon L.I., Kunkel L.M., Beggs A.H. A splice site mutation in laminin-a2 results in severe muscular dystrophy and growth abnormalities in zebrafish.PLoS One 7(8):e43794 (2012)
Marangi G., Orteschi D., Vigevano F., Felie J., Walsh C.A., Manzini M.C., Neri G. Expanding the spectrum of rearrangements involving chromosome 19: a mild phenotype associated with a 19p13.12-p13.13 deletion. Am J Med Genet 158A(4):888-93 (2012)
DiBlasi C., Bellafiore E., Salih M.A.M, Manzini M.C., Moore S.A., Seidahmed M.Z., Karrar Z.A., Walsh C.A., Campbell K.P., Mantegazza R., Morandi L, Mora M. Variable disease severity in Saudi Arabian and Sudanese families with c.3924+2T>C mutation of LAMA2. BMC Research Notes 4:534 (2011)
Labelle-Dumais C., Dilworth D.J., Harrington E.P., de Leau M., Lyons D., Kabaeva Z., Manzini M.C., Dobyns W.B., Walsh C.A., Michele D.E., Gould D.B. COL4A1 mutations cause ocular dysgenesis, neuronal localization defects and myopathy in mice and Walker Warburg Syndrome in humans. PLoS Genet 7(5):e1002062 (2011)
Manzini M.C., Walsh C.A. What disorders of cortical development tell us about the cortex: one plus one does not always make two. Curr Op Genet Dev 21(3):333-339 (2011)
Manzini M.C. Changing society starting from education (in Italian), in Terza Cultura: Idee per un futuro sostenibile, edited by V. Lingiardi and N. Vassallo, Il Saggiatore, Milano (2011)
Featured in Nature Medicine News: Dolgin E. Jewish genetic screening grows despite questions about breadth. Nat Med 17:639 (2011)
Birk E., Har-Zahav A., Manzini M.C., Pasmarnik-Chor M., Konreich L., Walsh C.A., Noben-Trauth, K., Albin A., Simon A.J., Collaux S., Morad Y., Reinshtein D., Tischfield D., Wang P., Magal N., Maya I., Shoshani N., Rehavi G., Gothelf D., Shohat M., Basel-Vanagaite L. A mutation in the SOBP gene causes syndromic and non-syndromic mental retardation and is highly expressed in the brain limbic system. Am J Hum Genet 87(5):694-700 (2010)
Manzini M.C.*, Rajab A.*, Maynard T.M., Mochida G.H., Tan W-H., Nasir R., Hill R.S., Gleason D., Al Saffar M., Partlow J.N., Barry B.J., Vernon M., LaMantia A-S, Walsh C.A. Developmental and degenerative features in a complicated spastic paraplegia. Ann Neurol 67(4):516-525 (2010) * contributed equally
Lee H.Y., Greene L.A., Mason C.A., Manzini M.C. Isolation and culture of mouse cerebellar granule neuron progenitor cells and neurons. J Vis Exp 23 pii:990, doi:10.3791/990 (2009) More than 33,000 views as of June 2013
Manzini M.C., Gleason D., Chang B.S., Hill R.S., Barry B.J., Partlow J.N., Poduri A., Currier S., Galvin-Parton P., Shapiro L.R., Schmidt K., Davis J.G., Basel-Vanagaite L., Seidahmed M.Z., Salih M., Dobyns W.B., Walsh C.A. Ethnically diverse causes of Walker Warburg Syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East. Hum Mut 29(11): E231-241 (2008)
Rajab A.*, Manzini M.C.*, Mochida G.H., Walsh C.A., Ross M.E. A novel form of lethal microcephaly with simplified gyral pattern and brain stem hypoplasia. Am J Med Genet 143(23): 2761-2767 (2007) * contributed equally
Industry Relationships and Collaborations
This faculty member (or a member of their immediate family) has reported a financial interest with the health care related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.