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Haruo Okado
The mechanisms regulating the formation of the cerebral cortex have been well studied. In the developing cortex, (also known Znf238, Zfp238, and Zbtb18), which encodes a sequence-specific transcriptional repressor, is expressed in glutamatergic projection neurons and progenitor cells. Targeted deletion of Rp58 leads to dysplasia of the neocortex and hippocampus, a reduction in the number of mature cortical neurons, and defects in laminar organization due to abnormal neuronal migration within the cortical plate...
March 1, 2018: Brain Research
Vita Fedele, Fangping Dai, Anie P Masilamani, Dieter H Heiland, Eva Kling, Ana M Gätjens-Sanchez, Roberto Ferrarese, Leonardo Platania, Doostkam Soroush, Hyunsoo Kim, Sven Nelander, Astrid Weyerbrock, Marco Prinz, Andrea Califano, Antonio Iavarone, Markus Bredel, Maria S Carro
Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation...
August 2017: Molecular Cancer Research: MCR
Olivier Clément, Isabel Anne Hemming, Ivan Enghian Gladwyn-Ng, Zhengdong Qu, Shan Shan Li, Michael Piper, Julian Ik-Tsen Heng
BACKGROUND: During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised. FINDINGS: Here, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27kip1 is important for E14...
May 15, 2017: Neural Development
Yoel Bogoch, Gilgi Friedlander-Malik, Lior Lupu, Ekaterina Bondar, Nitzan Zohar, Sheila Langier, Zvi Ram, Ido Nachmany, Joseph M Klausner, Niv Pencovich
Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. A mesenchymal phenotype was associated with tumor aggressiveness and poor prognosis in glioblastoma multiforme patients. Recently, the transcription factor RUNX1 was suggested as a driver of the glioblastoma multiforme mesenchymal gene expression signature; however, its independent role in this process is yet to be described. Here, we assessed the role of RUNX1 in U87 glioblastoma multiforme cells in correspondence to its mediated transcriptome and genome-wide occupancy pattern...
April 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
J S Cohen, S Srivastava, K D Farwell Hagman, D N Shinde, R Huether, D Darcy, R Wallerstein, G Houge, S Berland, K G Monaghan, A Poretti, A L Wilson, W K Chung, A Fatemi
Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations)...
May 2017: Clinical Genetics
Fátima Lopes, Mafalda Barbosa, Adam Ameur, Gabriela Soares, Joaquim de Sá, Ana Isabel Dias, Guiomar Oliveira, Pedro Cabral, Teresa Temudo, Eulália Calado, Isabel Fineza Cruz, José Pedro Vieira, Renata Oliveira, Sofia Esteves, Sascha Sauer, Inger Jonasson, Ann-Christine Syvänen, Ulf Gyllensten, Dalila Pinto, Patrícia Maciel
BACKGROUND: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. METHODS AND RESULTS: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants...
March 2016: Journal of Medical Genetics
L Lu, X M Chen, H M Tao, W Xiong, S H Jie, H Y Li
Microvesicles (MVs) are submicrometric membrane fragments that can "engulf" cytoplasmic contents such as microRNAs (miRNAs) from their cellular origin. The study of miRNAs carried within MVs might provide insights into the roles that miRNAs play in the underlying pathophysiologic processes of acute lymphoblastic leu-kemia (ALL). We identified numerous dysregulated MV miRNAs in patients with B- and T-cell ALL by using Agilent microarray analysis. Selected miRNAs obtained by microarray profiling were validated us-ing quantitative reverse transcription-polymerase chain reaction...
2015: Genetics and Molecular Research: GMR
Nicolas Diotel, Tanja Beil, Uwe Strähle, Sepand Rastegar
Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas...
September 2015: Gene Expression Patterns: GEP
Anastasios Mastrokolias, Yavuz Ariyurek, Jelle J Goeman, Erik van Duijn, Raymund A C Roos, Roos C van der Mast, GertJan B van Ommen, Johan T den Dunnen, Peter A C 't Hoen, Willeke M C van Roon-Mom
With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past...
October 2015: European Journal of Human Genetics: EJHG
Kohei Miyata, Tomoko Miyata, Kazuhiko Nakabayashi, Kohji Okamura, Masashi Naito, Tomoko Kawai, Shuji Takada, Kiyoko Kato, Shingo Miyamoto, Kenichiro Hata, Hiroshi Asahara
Although DNA methylation is considered to play an important role during myogenic differentiation, chronological alterations in DNA methylation and gene expression patterns in this process have been poorly understood. Using the Infinium HumanMethylation450 BeadChip array, we obtained a chronological profile of the genome-wide DNA methylation status in a human myoblast differentiation model, where myoblasts were cultured in low-serum medium to stimulate myogenic differentiation. As the differentiation of the myoblasts proceeded, their global DNA methylation level increased and their methylation patterns became more distinct from those of mesenchymal stem cells...
January 15, 2015: Human Molecular Genetics
Sonja A de Munnik, Sixto García-Miñaúr, Alexander Hoischen, Bregje W van Bon, Kym M Boycott, Jeroen Schoots, Lies H Hoefsloot, Nine V A M Knoers, Ernie M H F Bongers, Han G Brunner
The phenotype of patients with a chromosome 1q43q44 microdeletion (OMIM; 612337) is characterized by intellectual disability with no or very limited speech, microcephaly, growth retardation, a recognizable facial phenotype, seizures, and agenesis of the corpus callosum. Comparison of patients with different microdeletions has previously identified ZBTB18 (ZNF238) as a candidate gene for the 1q43q44 microdeletion syndrome. Mutations in this gene have not yet been described. We performed exome sequencing in a patient with features of the 1q43q44 microdeletion syndrome that included short stature, microcephaly, global developmental delay, pronounced speech delay, and dysmorphic facial features...
June 2014: European Journal of Human Genetics: EJHG
Julian Ik-Tsen Heng, Zhengdong Qu, Chiaki Ohtaka-Maruyama, Haruo Okado, Masataka Kasai, Diogo Castro, François Guillemot, Seong-Seng Tan
The zinc finger transcription factor RP58 (also known as ZNF238) regulates neurogenesis of the mouse neocortex and cerebellum (Okado et al. 2009; Xiang et al. 2011; Baubet et al. 2012; Ohtaka-Maruyama et al. 2013), but its mechanism of action remains unclear. In this study, we report a cell-autonomous function for RP58 during the differentiation of embryonic cortical projection neurons via its activities as a transcriptional repressor. Disruption of RP58 expression alters the differentiation of immature neurons and impairs their migration and positioning within the mouse cerebral cortex...
March 2015: Cerebral Cortex
Seth J Perlman, Shashikant Kulkarni, Linda Manwaring, Marwan Shinawi
A variety of candidate genes have been proposed to cause corpus callosum abnormalities (CCAs) in patients with terminal chromosome 1q deletions. Recent data excluded AKT3 and implicated ZNF238 and/or CEP170 as genes causative of corpus callosum anomalies in patients with 1q43-1q44 deletions. We report on a girl with dysmorphic features, seizures beginning in infancy, hypotonia, marked developmental delay, and dysgenesis of the corpus callosum. Chromosomal microarray analysis detected a de novo 1.47 Mb deletion at 1q44...
April 2013: American Journal of Medical Genetics. Part A
Gaelle Thierry, Claire Bénéteau, Olivier Pichon, Elisabeth Flori, Bertrand Isidor, Françoise Popelard, Marie-Ange Delrue, Laetitia Duboscq-Bidot, Ann-Charlotte Thuresson, Bregje W M van Bon, Dorothée Cailley, Caroline Rooryck, Agathe Paubel, Corinne Metay, Anne Dusser, Laurent Pasquier, Mylène Béri, Céline Bonnet, Sylvie Jaillard, Christèle Dubourg, Bassim Tou, Marie-Pierre Quéré, Cecilia Soussi-Zander, Annick Toutain, Didier Lacombe, Benoit Arveiler, Bert B A de Vries, Philippe Jonveaux, Albert David, Cédric Le Caignec
Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies...
July 2012: American Journal of Medical Genetics. Part A
Kyle L Macquarrie, Zizhen Yao, Janet M Young, Yi Cao, Stephen J Tapscott
BACKGROUND: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation...
April 29, 2012: Skeletal Muscle
Valérie Baubet, Chaomei Xiang, Aliah Molczan, Laura Roccograndi, Svetlana Melamed, Nadia Dahmane
Cerebellum development depends on the correct differentiation of progenitors into neurons, a process controlled by a transcriptional program that remains poorly understood. Here we show that neural-specific deletion of the BTB/POZ zinc-finger transcription factor-encoding gene Rp58 (Znf238, Zfp238) causes severe cerebellar hypoplasia and developmental failure of Purkinje neurons, Bergmann glia and granule neurons. Deletion of Rp58 in mouse embryonic Atoh1(+) progenitors leads to strong defects in growth and foliation owing to its crucial role in the differentiation of granule neurons...
June 2012: Development
C Xiang, V Baubet, S Pal, L Holderbaum, V Tatard, P Jiang, R V Davuluri, N Dahmane
Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human...
April 2012: Cell Death and Differentiation
Sandesh C Sreenath Nagamani, Ayelet Erez, Carolyn Bay, Anjana Pettigrew, Seema R Lalani, Kristin Herman, Brett H Graham, Malgorzata Jm Nowaczyk, Monica Proud, William J Craigen, Bobbi Hopkins, Beth Kozel, Katie Plunkett, Patricia Hixson, Pawel Stankiewicz, Ankita Patel, Sau Wai Cheung
Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44...
February 2012: European Journal of Human Genetics: EJHG
Blake C Ballif, Jill A Rosenfeld, Ryan Traylor, Aaron Theisen, Patricia I Bader, Roger L Ladda, Susan L Sell, Michelle Steinraths, Urvashi Surti, Marianne McGuire, Shelley Williams, Sandra A Farrell, James Filiano, Rhonda E Schnur, Lauren B Coffey, Raymond C Tervo, Tracy Stroud, Michael Marble, Michael Netzloff, Kristen Hanson, Arthur S Aylsworth, J S Bamforth, Deepti Babu, Dmitriy M Niyazov, J Britt Ravnan, Roger A Schultz, Allen N Lamb, Beth S Torchia, Bassem A Bejjani, Lisa G Shaffer
Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes...
January 2012: Human Genetics
Almuth Caliebe, Hester Y Kroes, Jasper J van der Smagt, José I Martin-Subero, Holger Tönnies, Ruben van 't Slot, Rutger A J Nievelstein, Hiltrud Muhle, Ulrich Stephani, Karsten Alfke, Irina Stefanova, Yorck Hellenbroich, Gabriele Gillessen-Kaesbach, Ron Hochstenbach, Reiner Siebert, Martin Poot
Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them...
July 2010: European Journal of Medical Genetics
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