Browsing by Author "Louvi, Angeliki"

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Integrated genomic characterization of IDH1-mutant glioma malignant progression
(NATURE PUBLISHING GROUP, 2016-01-01) Bai, Hanwen; Harmanci, Akdes Serin; Erson-Omay, E. Zeynep; Li, Jie; Coskun, Sueleyman; Simon, Matthias; Krischek, Boris; Ozduman, Koray; Omay, S. Buelent; Sorensen, Eric A.; Turcan, Sevin; Bakirciglu, Mehmet; Carrion-Grant, Geneive; Murray, Phillip B.; Clark, Victoria E.; Ercan-Sencicek, A. Gulhan; Knight, James; Sencar, Leman; Altinok, Selin; Kaulen, Leon D.; Guelez, Burcu; Timmer, Marco; Schramm, Johannes; Mishra-Gorur, Ketu; Henegariu, Octavian; Moliterno, Jennifer; Louvi, Angeliki; Chan, Timothy A.; Tannheimer, Stacey L.; Pamir, M. Necmettin; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; Guenel, Murat
Gliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
Recessive LAMC3 mutations cause malformations of occipital cortical development
(NATURE PUBLISHING GROUP, 2011-01-01) Barak, Tanyeri; Kwan, Kenneth Y.; Louvi, Angeliki; Demirbilek, Veysi; Saygi, Serap; Tuysuz, Beyhan; Choi, Murim; Boyaci, Huseyin; Doerschner, Katja; Zhu, Ying; Kaymakcalan, Hande; Yilmaz, Saliha; Bakircioglu, Mehmet; Caglayan, Ahmet Okay; Oeztuerk, Ali Kemal; Yasuno, Katsuhito; Brunken, William J.; Atalar, Ergin; Yalcinkaya, Cengiz; Dincer, Alp; Bronen, Richard A.; Mane, Shrikant; Ozcelik, Tayfun; Lifton, Richard P.; Sestan, Nenad; Bilguevar, Kaya; Guenel, Murat
The biological basis for regional and inter-species differences in cerebral cortical morphology is poorly understood. We focused on consanguineous Turkish families with a single affected member with complex bilateral occipital cortical gyration abnormalities. By using whole-exome sequencing, we initially identified a homozygous 2-bp deletion in LAMC3, the laminin. 3 gene, leading to an immediate premature termination codon. In two other affected individuals with nearly identical phenotypes, we identified a homozygous nonsense mutation and a compound heterozygous mutation. In human but not mouse fetal brain, LAMC3 is enriched in postmitotic cortical plate neurons, localizing primarily to the somatodendritic compartment. LAMC3 expression peaks between late gestation and late infancy, paralleling the expression of molecules that are important in dendritogenesis and synapse formation. The discovery of the molecular basis of this unusual occipital malformation furthers our understanding of the complex biology underlying the formation of cortical gyrations.
Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration
(NATL ACAD SCIENCES, 2013-01-01) Bilguvar, Kaya; Tyagi, Navneet K.; Ozkara, Cigdem; Tuysuz, Beyhan; Bakircioglu, Mehmet; Choi, Murim; Delil, Sakir; Caglayan, Ahmet O.; Baranoski, Jacob F.; Erturk, Ozdem; Yalcinkaya, Cengiz; Karacorlu, Murat; Dincer, Alp; Johnson, Michele H.; Mane, Shrikant; Chandra, Sreeganga S.; Louvi, Angeliki; Boggon, Titus J.; Lifton, Richard P.; Horwich, Arthur L.; Gunel, Murat
Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific deubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1(GLU7ALA).), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1(GLU7ALA), compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1(GLU7ALA) relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system.
Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations
(NATURE PUBLISHING GROUP, 2010-01-01) Bilguvar, Kaya; Ozturk, Ali Kemal; Louvi, Angeliki; Kwan, Kenneth Y.; Choi, Murim; Tatli, Burak; Yalnizoglu, Dilek; Tuysuz, Beyhan; Caglayan, Ahmet Okay; Gokben, Sarenur; Kaymakcalan, Hande; Barak, Tanyeri; Bakircioglu, Mehmet; Yasuno, Katsuhito; Ho, Winson; Sanders, Stephan; Zhu, Ying; Yilmaz, Sanem; Dincer, Alp; Johnson, Michele H.; Bronen, Richard A.; Kocer, Naci; Per, Hueseyin; Mane, Shrikant; Pamir, Mehmet Necmettin; Yalcinkaya, Cengiz; Kumandas, Sefer; Topcu, Meral; Ozmen, Meral; Sestan, Nenad; Lifton, Richard P.; State, Matthew W.; Gunel, Murat
The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers(1,2). An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development(3-6). Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.