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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)...
September 6, 2016: 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...
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
C Orellana, M Roselló, S Monfort, S Oltra, R Quiroga, I Ferrer, F Martínez
Submicroscopic deletions of 1q44-qter cause severe mental retardation, profound growth retardation, microcephaly and corpus callosum hypo/agenesis in most patients. At least 3 intervals in 1q44 have been described as critical regions containing genes leading to corpus callosum abnormalities. In this report we describe a patient with a de novo small interstitial 1q44 deletion of 1,152 kb detected with 44K oligonucleotide array-CGH (44K Agilent Technologies) and a mild phenotype lacking corpus callosum abnormalities...
2009: Cytogenetic and Genome Research
Valérie M Tatard, Chaomei Xiang, Jaclyn A Biegel, Nadia Dahmane
Brain tumors such as medulloblastoma (MB) and glioblastoma multiforme (GBM) can derive from neural precursors. For instance, many MBs are thought to arise from the uncontrolled proliferation of cerebellar granule neuron precursors (GNP). GNPs normally proliferate in early postnatal stages in mice but then they become postmitotic and differentiate into granule neurons. The proliferation of neural precursors, GNPs, as well as at least subsets of GBM and MB depends on Hedgehog signaling. However, the gene functions that are lost or suppressed in brain tumors and that normally promote the proliferation arrest and differentiation of precursors remain unclear...
February 1, 2010: Cancer Research
Won Kim, Sunmi Kim, Hojun Choi, Nguyen Dinh Truong, Le Minh Thong, Jin-Hoi Kim, Rui Xiao, Keun-Kyu Park, Kunho Seo, Hang Lee, Bo-Sook Kim, Mi-Hyun Yoo, Chankyu Park
We screened 3750 single exonic genes listed in the intronless genes in the eukaryotes (SEGE) database and performed bioinformatic analyses to identify candidate genes for new species-specific markers. A set of PCR primers for the conserved regions of ZNF238 was developed and used to amplify the 823 bp DNA fragment. We compared nucleotide variations of the PCR products among 20 species plus two subspecies of animals, which led to the identification of interspecies nucleotide variations. To establish a simple method for the analysis of species-specific DNA polymorphisms using ZNF238, we developed a PCR-RFLP method using HhaI and HpyCH4IV restriction enzymes for 13 species...
February 24, 2010: Journal of Agricultural and Food Chemistry
Ivan Martinez, Jun Wang, Kenosha F Hobson, Robert L Ferris, Saleem A Khan
Human papillomaviruses (HPVs) have been implicated in the pathogenesis of a subset of squamous cell carcinoma of the head and neck (SCCHN). The goal of this study was to compare the cellular gene expression profiles of HPV-positive and HPV-negative oropharyngeal carcinomas with those of the normal oral epithelium. Using Affymetrix Human U133A GeneChip, our results showed that 397 genes were differentially expressed in HPV-positive SCCHN compared to the normal oral epithelium. The upregulated genes included those involved in cell cycle regulation (CDKN2A), cell differentiation (SFRP4) and DNA repair (RAD51AP1), while the downregulated genes included those involved in proteolysis (PRSS3)...
January 2007: European Journal of Cancer
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