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Item The Essential Role of Centrosomal NDE1 in Human Cerebral Cortex Neurogenesis(CELL PRESS, 2011-01-01) Bakircioglu, Mehmet; Carvalho, Ofelia P.; Khurshid, Maryam; Cox, James J.; Tuysuz, Beyhan; Barak, Tanyeri; Yilmaz, Saliha; Caglayan, Okay; Dincer, Alp; Nicholas, Adeline K.; Quarrell, Oliver; Springell, Kelly; Karbani, Gulshan; Malik, Saghira; Gannon, Caroline; Sheridan, Eamonn; Crosier, Moira; Lisgo, Steve N.; Lindsay, Susan; Bilguvar, Kaya; Gergely, Fanni; Gunel, Murat; Woods, C. GeoffreyWe investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10\% of expected size (<= 10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination tinicrolissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684\_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684\_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.Item 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, MuratThe 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.Item 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, MuratThe 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.Item Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO(AMER ASSOC ADVANCEMENT SCIENCE, 2013-01-01) Clark, Victoria E.; Erson-Omay, E. Zeynep; Serin, Akdes; Yin, Jun; Cotney, Justin; Oezduman, Koray; Avsar, Timuin; Li, Jie; Murray, Phillip B.; Henegariu, Octavian; Yilmaz, Saliha; Guenel, Jennifer Moliterno; Carrion-Grant, Geneive; Yilmaz, Baran; Grady, Conor; Tanrikulu, Bahattin; Bakircioglu, Mehmet; Kaymakcalan, Hande; Caglayan, Ahmet Okay; Sencar, Leman; Ceyhun, Emre; Atik, A. Fatih; Bayri, Yasar; Bai, Hanwen; Kolb, Luis E.; Hebert, Ryan M.; Omay, S. Bulent; Mishra-Gorur, Ketu; Choi, Murim; Overton, John D.; Holland, Eric C.; Mane, Shrikant; State, Matthew W.; Bilguevar, Kaya; Baehring, Joachim M.; Gutin, Philip H.; Piepmeier, Joseph M.; Vortmeyer, Alexander; Brennan, Cameron W.; Pamir, M. Necmettin; Kilic, Tuerker; Lifton, Richard P.; Noonan, James P.; Yasuno, Katsuhito; Guenel, MuratWe report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation ( K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in similar to 5\% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.Item 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, MuratUbiquitin 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.Item Somatic POLE mutations cause an ultramutated giant cell high-grade glioma subtype with better prognosis(OXFORD UNIV PRESS INC, 2015-01-01) Erson-Omay, E. Zeynep; Caglayan, Ahmet Okay; Schultz, Nikolaus; Weinhold, Nils; Omay, S. Bulent; Ozduman, Koray; Koksal, Yavuz; Li, Jie; Harmanci, Akdes Serin; Clark, Victoria; Carrion-Grant, Geneive; Baranoski, Jacob; Caglar, Caner; Barak, Tanyeri; Coskun, Suleyman; Baran, Burcin; Kose, Dogan; Sun, Jia; Bakircioglu, Mehmet; Gunel, Jennifer Moliterno; Pamir, M. Necmettin; Mishra-Gorur, Ketu; Bilguvar, Kaya; Yasuno, Katsuhito; Vortmeyer, Alexander; Huttner, Anita J.; Sander, Chris; Gunel, MuratBackground. Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods. We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results. We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these ``ultramutated{''} tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions. We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.Item Longitudinal analysis of treatment-induced genomic alterations in gliomas(BIOMED CENTRAL LTD, 2017-01-01) Erson-Omay, E. Zeynep; Henegariu, Octavian; Omay, S. Bulent; Harmanci, Akdes Serin; Youngblood, Mark W.; Mishra-Gorur, Ketu; Li, Jie; Ozduman, Koray; Carrion-Grant, Geneive; Clark, Victoria E.; Caglar, Caner; Bakircioglu, Mehmet; Pamir, M. Necmettin; Tabar, Viviane; Vortmeyer, Alexander O.; Bilguvar, Kaya; Yasuno, Katsuhito; DeAngelis, Lisa M.; Baehring, Joachim M.; Moliterno, Jennifer; Gunel, MuratBackground: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy