Araştırma Çıktıları

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    A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling
    (OXFORD UNIV PRESS, 2013-01-01) Wieczorek, Dagmar; Boegershausen, Nina; Beleggia, Filippo; Steiner-Haldenstaett, Sabine; Pohl, Esther; Li, Yun; Milz, Esther; Martin, Marcel; Thiele, Holger; Altmueller, Janine; Alanay, Yasemin; Kayserili, Hulya; Klein-Hitpass, Ludger; Bohringer, Stefan; Wollstein, Andreas; Albrecht, Beate; Boduroglu, Koray; Caliebe, Almuth; Chrzanowska, Krystyna; Cogulu, Ozgur; Cristofoli, Francesca; Czeschik, Johanna Christina; Devriendt, Koenraad; Dotti, Maria Teresa; Elcioglu, Nursel; Gener, Blanca; Goecke, Timm O.; Krajewska-Walasek, Malgorzata; Guillen-Navarro, Encarnacion; Hayek, Joussef; Houge, Gunnar; Kilic, Esra; Simsek-Kiper, Pelin Ozlem; Lopez-Gonzalez, Vanesa; Kuechler, Alma; Lyonnet, Stanislas; Mari, Francesca; Marozza, Annabella; Dramard, Michele Mathieu; Mikat, Barbara; Morin, Gilles; Morice-Picard, Fanny; Ozkinay, Ferda; Rauch, Anita; Renieri, Alessandra; Tinschert, Sigrid; Utine, G. Eda; Vilain, Catheline; Vivarelli, Rossella; Zweier, Christiane; Nuernberg, Peter; Rahmann, Sven; Vermeesch, Joris; Luedecke, Hermann-Josef; Zeschnigk, Michael; Wollnik, Bernd
    Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs{*}53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60\% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76\% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.
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    Further characterization of ATP6V0A2-related autosomal recessive cutis laxa
    (SPRINGER, 2012-01-01) Fischer, Bjoern; Dimopoulou, Aikaterini; Egerer, Johannes; Gardeitchik, Thatjana; Kidd, Alexa; Jost, Dominik; Kayserili, Hulya; Alanay, Yasemin; Tantcheva-Poor, Iliana; Mangold, Elisabeth; Daumer-Haas, Cornelia; Phadke, Shubha; Peirano, Reto I.; Heusel, Julia; Desphande, Charu; Gupta, Neerja; Nanda, Arti; Felix, Emma; Berry-Kravis, Elisabeth; Kabra, Madhulika; Wevers, Ron A.; van Maldergem, Lionel; Mundlos, Stefan; Morava, Eva; Kornak, Uwe
    Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debr, type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H+-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-beta signalling and increased TGF-beta 1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.
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    Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis
    (WILEY, 2013-01-01) Keupp, Katharina; Li, Yun; Vargel, Ibrahim; Hoischen, Alexander; Richardson, Rebecca; Neveling, Kornelia; Alanay, Yasemin; Uz, Elif; Elcioglu, Nursel; Rachwalski, Martin; Kamaci, Soner; Tuncbilek, Gokhan; Akin, Burcu; Grotzinger, Joachim; Konas, Ersoy; Mavili, Emin; Muller-Newen, Gerhard; Collmann, Hartmut; Roscioli, Tony; Buckley, Michael F.; Yigit, Gokhan; Gilissen, Christian; Kress, Wolfram; Veltman, Joris; Hammerschmidt, Matthias; Akarsu, Nurten A.; Wollnik, Bernd
    We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation
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    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.
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    Interpratation and Adaptation of Dermoscopic Terminology to Our Language: Consensus Report of the Turkish Society of Dermatology Dermoscopy Working Group
    (GALENOS YAYINCILIK, 2013-01-01) Ozdemir, Fezal; Karaarslan, Isil Kilinc; Turk, Bengu Gerceker; Sahin, Sedef; Sahin, Mustafa Turhan; Oguz, Oya; Oztas, Murat Orhan; Arca, Ercan; Mansur, Tulin; Karabulut, Ayse Anil; Kacar, Nida
    ``Dermoscopic Terminology Consensus Meeting{''} was held at Ege University Medical Faculty Dermatology Department on the 24th of February in 2012 with the aim of establishing a common language in the translation of the dermoscopic terminology in English literature into Turkish. In this article, the Turkish terminology in which the consensus was reached at that meeting is presented together with the definitions and representative images as a dictionary.
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    The effects of pegylated interferon alpha 2b on bile-duct ligation induced liver fibrosis in rats
    (MEXICAN ASSOC HEPATOLOGY, 2009-01-01) Canbakan, Billur; Akin, Hakan; Tahan, Gulgun; Tarcin, Orhan; Eren, Fatih; Atug, Ozlen; Tahan, Veysel; Imeryuz, Nese; Yapicier, Ozlem; Avsar, Erol; Tozun, Nurdan
    Objective. To test the effects of peginterferon in an unrecoverable model of bite-duct ligation (BDL) induced liver fibrosis. Material and methods. Thirty-seven Wistar rats were divided into five groups: group 1, BDL + peginterferon (n = 8)
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    High-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis
    (NEOPLASIA PRESS, 2012-01-01) Diaz, Roberto Jose; Guduk, Mustafa; Romagnuolo, Rocco; Smith, Christian A.; Northcott, Paul; Shih, David; Berisha, Fitim; Flanagan, Adrienne; Munoz, David G.; Cusimano, Michael D.; Pamir, M. Necmettin; Rutka, James T.
    Chordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemo-therapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22\%) than previously reported for sacral chordoma. At a similar frequency (21\%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98\% of sacral chordomas and 67\% of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm. Neoplasia (2012) 14, 788-798
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    Dobrava Hantavirus Infection Complicated by Panhypopituitarism, Istanbul, Turkey, 2010
    (CENTERS DISEASE CONTROL, 2012-01-01) Sariguzel, Nevin; Hofmann, Joerg; Canpolat, Alper Tunga; Turk, Ali; Ettinger, Jakob; Atmaca, Deniz; Akyar, Isin; Yucel, Serap; Arikan, Ender; Uyar, Yavuz; Caglayik, Dilek Y.; Kocagoz, Ayse Sesin; Kaya, Aysin; Kruger, Detlev H.
    We identified Dobrava-Belgrade virus infection in Turkey (from a strain related to hantavirus strains from nearby countries) in a patient who had severe symptoms leading to panhypopituitarism, but no known risk for hantavirus. Our findings emphasize the need for increased awareness of hantaviruses in the region and assessment of symptomatic persons without known risk factors for infection.
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    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, Murat
    We 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.
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    Detection of KIAA1549-BRAF Fusion Transcripts in Formalin-Fixed Paraffin-Embedded Pediatric Low-Grade Gliomas
    (ELSEVIER SCIENCE INC, 2011-01-01) Tian, Yongji; Rich, Benjamin E.; Vena, Natalie; Craig, Justin M.; MacConaill, Laura E.; Rajaram, Veena; Goldman, Stewart; Taha, Hala; Mahmoud, Madeha; Ozek, Memet; Sav, Aydin; Longtine, Janina A.; Lindeman, Neal I.; Garraway, Levi A.; Ligon, Azra H.; Stiles, Charles D.; Santagata, Sandra; Chan, Jennifer A.; Kieran, Mark W.; Ligon, Keith L.
    Alterations of BRAF are the most common known genetic aberrations in pediatric gliomas. They frequently are found in pilocytic astrocytomas, where genomic duplications involving BRAF and the poorly characterized gene KIAA1549 create fusion proteins with constitutive B-Raf kinase activity. BRAF V600E point mutations are less common and generally occur in nonpilocytic tumors. The development of BRAF inhibitors as drugs has created an urgent need for robust clinical assays to identify activating lesions in BRAF. KIAA1549-BRAF fusion transcripts have been detected in frozen tissue, however, methods for FFPE tissue have not been reported. We developed a panel of FFPE-compatible quantitative RT-PCR assays for the most common KIAA1549-BRAF fusion transcripts. Application of these assays to a collection of 51 low-grade pediatric gliomas showed 97\% sensitivity and 91\% specificity compared with fluorescence in situ hybridization or array comparative genomic hybridization. In parallel, we assayed samples for the presence of the BRAF V600E mutation by PCR pyrosequencing. The data further support previous observations that these two alterations of the BRAF, KIAA1549 fusions and V600E point mutations, are associated primarily with pilocytic astrocytomas and nonpilocytic gliomas, respectively. These results show that fusion transcripts and mutations can be detected reliably in standard FFPE specimens and may be useful for incorporation into future studies of pediatric gliomas in basic science or clinical trials. (J Mal Diagn 2011, 13:669-677