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Ganesh, Vijay

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Ganesh

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Vijay

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Ganesh, Vijay
Author's Publications: search.filters.isAuthorOfPublication.d7bfe1c0-413b-4012-b235-292884062974

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    Identification and Characterization of Genes Essential for Human Brain Development
    (2012-10-18) Ganesh, Vijay; Walsh, Christopher A.; Corfas, Gabriel; Ross, Margaret; Piao, Xianhua; Sahin, Mustafa
    The human brain is a network of ninety billion neurons that allows for many of the behavioral adaptations considered unique to our species. One-fifth of these neurons are layered in an epithelial sheet known as the cerebral cortex, which is exquisitely folded into convolutions called gyri. Defects in neuronal number clinically present with microcephaly (Greek for “small head”), and in inherited cases these defects can be linked to mutations that identify genes essential for neural progenitor proliferation. Most microcephaly genes are characterized to play a role in the centrosome, however rarer presentations of microcephaly have identified different mechanisms. Charged multivesicular body protein/Chromatin modifying protein 1A (CHMP1A) is a member of the ESCRT-III endosomal sorting complex, but is also suggested to localize to the nuclear matrix and regulate chromatin. We show that loss-of-function mutations to human CHMP1A cause a rare microcephaly syndrome with reduced cerebellar volume. CHMP1A mutant cells show impaired proliferation, with increased expression of INK4A, a negative regulator of stem cell proliferation, and loss of enrichment of INK4A promoter DNA in chromatin immunoprecipitations performed against BMI1, indicating a loss of the normal repression of INK4A by BMI1. Defects in zebrafish produced by morpholino-based knockdown of the CHMP1A orthologue resembled those seen after bmi1 knockdown, and were partially rescued by INK4A orthologue knockdown. Chmp1a is expressed in dividing cells in the developing cerebral cortex and cerebellar external germinal layer, and in vitro knockdown assays using short hairpin RNA implicate a role in Wnt- and Shh-pathway signal transduction. Altogether, this suggests that CHMP1A serves as a critical link between cytoplasmic and nuclear signals that regulate neural progenitor proliferation. Compared to microcephaly, polymicrogyria is a more heterogeneous brain malformation that has been suggested to implicate molecular mechanisms involved in pattern formation in the cortex. Many cases of polymicrogyria show an asymmetric distribution, and we demonstrate that these cases are strongly biased towards a right-predominant pattern. Using whole-exome sequencing in patients with polymicrogyria, we identify rare mutations in two primary microcephaly genes, ASPM and WDR62. Interestingly, some of these patients lack profound microcephaly, suggesting heretofore underappreciated pleiotropic effects of these centrosomal genes.
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    CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development
    (2013) Mochida, Ganeshwaran; Ganesh, Vijay; de Michelena, Maria I.; Dias, Hugo; Atabay, Kutay D.; Kathrein, Katie L.; Huang, Emily; Hill, Robert; Felie, Jillian M.; Rakiec, Daniel; Gleason, Danielle; Hill, Anthony D.; Malik, Athar; Barry, Brenda J.; Partlow, Jennifer; Tan, Wen-Hann; Glader, Laurie; Barkovich, A. James; Dobyns, William B.; Zon, Leonard; Walsh, Christopher
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    Rapid Detection of Powassan Virus in a Patient With Encephalitis by Metagenomic Sequencing
    (Oxford University Press, 2017) Piantadosi, Anne; Kanjilal, Sanjat; Ganesh, Vijay; Khanna, Arjun; Hyle, Emily; Rosand, Jonathan; Bold, Tyler; Metsky, Hayden C; Lemieux, Jacob; Leone, Michael J; Freimark, Lisa; Matranga, Christian B; Adams, Gordon; McGrath, Graham; Zamirpour, Siavash; Telford, Sam; Rosenberg, Eric; Cho, Tracey Alexander; Frosch, Matthew; Goldberg, Marcia; Mukerji, Shibani; Sabeti, Pardis
    Abstract We describe a patient with severe and progressive encephalitis of unknown etiology. We performed rapid metagenomic sequencing from cerebrospinal fluid and identified Powassan virus, an emerging tick-borne flavivirus that has been increasingly detected in the United States.