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Search Results: 1 - 10 of 40573 matches for " Hans van Bokhoven "
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Regulation of MYCN expression in human neuroblastoma cells
Joannes FM Jacobs, Hans van Bokhoven, Frank N van Leeuwen, Christina A Hulsbergen-van de Kaa, I de Vries, Gosse J Adema, Peter M Hoogerbrugge, Arjan PM de Brouwer
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-239
Abstract: Expression of MYCN, MYCNOS and ΔMYCN was measured in human NB tissues of different stages. Transcript levels were quantified using a real-time reverse transcriptase polymerase chain reaction assay (QPCR). In addition, relative expression of these three transcripts was compared to the number of MYCN copies, which was determined by genomic real-time PCR (gQPCR).Both ΔMYCN and MYCNOS are expressed in all NBs examined. In NBs with MYCN-amplification, these transcripts are significantly higher expressed. The ratio of MYCN:ΔMYCN expression was identical in all tested NBs. This indicates that ΔMYCN and MYCN are co-regulated, which suggests that ΔMYCN is not a regulator of MYCN in NB. However, the ratio of MYCNOS:MYCN expression is directly correlated with NB disease stage (p = 0.007). In the more advanced NB stages and NBs with MYCN-amplification, relatively more MYCNOS is present as compared to MYCN. Expression of the antisense gene MYCNOS might be relevant to the progression of NB, potentially by directly inhibiting MYCN transcription by transcriptional interference at the DNA level.The MYCNOS:MYCN-ratio in NBs is significantly correlated with both MYCN-amplification and NB-stage. Our data indicate that in NB, MYCN expression levels might be influenced by MYCNOS but not by ΔMYCN.Neuroblastoma cells (NBs) that carry an amplified MYCN gene are extremely malignant. However, MYCN-amplification does not automatically result in higher expression of MYCN in children with NB [1-3]. Thus, it has been suggested that the aggressive phenotype of MYCN amplified NBs may be explained by higher expression levels of other genes co-amplified with MYCN, since the amplified unit of DNA can be up to 1 Mb. To date, three genes have been identified that are frequently co-amplified with MYCN in NBs: DDX1 in 50% of the cases, NAG in 20% of the tumours, and MYCNOS in all cases [4,5]. All three genes demonstrate increased transcript expression when co-amplified in NB cell lines, indicating that th
Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a
Jamie M. Kramer,Korinna Kochinke,Merel A. W. Oortveld,Hendrik Marks,Daniela Kramer,Eiko K. de Jong,Zoltan Asztalos,J. Timothy Westwood,Hendrik G. Stunnenberg,Marla B. Sokolowski,Krystyna Keleman,Huiqing Zhou,Hans van Bokhoven,Annette Schenck
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000569
Abstract: The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the “writers” of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5′ and 3′ ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.
Epigenetic Regulation of Learning and Memory by Drosophila EHMT/G9a
Jamie M. Kramer,Korinna Kochinke,Merel A. W. Oortveld,Hendrik Marks,Daniela Kramer,Eiko K. de Jong,Zoltan Asztalos,J. Timothy Westwood,Hendrik G. Stunnenberg,Marla B. Sokolowski,Krystyna Keleman,Huiqing Zhou,Hans van Bokhoven ,Annette Schenck
PLOS Biology , 2011, DOI: 10.1371/journal.pbio.1000569
Abstract: The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the “writers” of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5′ and 3′ ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease.
Hydrogenation over gold catalysts: The interaction of gold with hydrogen
Christiane Kartusch,Jeroen A van Bokhoven
Gold Bulletin , 2009, DOI: 10.1007/BF03214957
Abstract: Gold is active in various hydrogenation reactions and often shows exceptional high chemoselectivity when multiple functional groups are present. All hydrogenation reactions have in common, that the hydrogen molecules have to adsorb and dissociate before they react. Recent insights in the interaction of gold with hydrogen and simple reactions involving hydrogen are described.
Autosomal Recessive Dilated Cardiomyopathy due to DOLK Mutations Results from Abnormal Dystroglycan O-Mannosylation
Dirk J. Lefeber equal contributor ,Arjan P. M. de Brouwer equal contributor,Eva Morava,Moniek Riemersma,Janneke H. M. Schuurs-Hoeijmakers,Birgit Absmanner,Kiek Verrijp,Willem M. R. van den Akker,Karin Huijben,Gerry Steenbergen,Jeroen van Reeuwijk,Adam Jozwiak,Nili Zucker,Avraham Lorber,Martin Lammens,Carlos Knopf,Hans van Bokhoven,Stephanie Grünewald,Ludwig Lehle,Livia Kapusta,Hanna Mandel ?,Ron A. Wevers ?
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002427
Abstract: Genetic causes for autosomal recessive forms of dilated cardiomyopathy (DCM) are only rarely identified, although they are thought to contribute considerably to sudden cardiac death and heart failure, especially in young children. Here, we describe 11 young patients (5–13 years) with a predominant presentation of dilated cardiomyopathy (DCM). Metabolic investigations showed deficient protein N-glycosylation, leading to a diagnosis of Congenital Disorders of Glycosylation (CDG). Homozygosity mapping in the consanguineous families showed a locus with two known genes in the N-glycosylation pathway. In all individuals, pathogenic mutations were identified in DOLK, encoding the dolichol kinase responsible for formation of dolichol-phosphate. Enzyme analysis in patients' fibroblasts confirmed a dolichol kinase deficiency in all families. In comparison with the generally multisystem presentation in CDG, the nonsyndromic DCM in several individuals was remarkable. Investigation of other dolichol-phosphate dependent glycosylation pathways in biopsied heart tissue indicated reduced O-mannosylation of alpha-dystroglycan with concomitant functional loss of its laminin-binding capacity, which has been linked to DCM. We thus identified a combined deficiency of protein N-glycosylation and alpha-dystroglycan O-mannosylation in patients with nonsyndromic DCM due to autosomal recessive DOLK mutations.
Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila
Merel A. W. Oortveld,Shivakumar Keerthikumar,Martin Oti,Bonnie Nijhof,Ana Clara Fernandes,Korinna Kochinke,Anna Castells-Nobau,Eva van Engelen,Thijs Ellenkamp,Lilian Eshuis,Anne Galy,Hans van Bokhoven,Bianca Habermann,Han G. Brunner,Christiane Zweier,Patrik Verstreken,Martijn A. Huynen,Annette Schenck
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003911
Abstract: Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.
Rapid Health and Needs assessments after disasters: a systematic review
Helena A Korteweg, Irene van Bokhoven, CJ Yzermans, Linda Grievink
BMC Public Health , 2010, DOI: 10.1186/1471-2458-10-295
Abstract: A review was conducted, including original studies concerning a rapid health and/or needs assessment. The studies used were published between 1980 and 2009. The electronic databasesof Medline, Embase, SciSearch and Psychinfo were used.Thirty-three studies were included for this review. The majority of the studies was of US origin and in most cases related to natural disasters, especially concerning the weather. In eighteen studies an assessment was conducted using a structured questionnaire, eleven studies used registries and four used both methods. Questionnaires were primarily used to asses the health needs, while data records were used to assess the health status of disaster victims.Methods most commonly used were face to face interviews and data extracted from existing registries. Ideally, a rapid assessment tool is needed which does not add to the burden of disaster victims. In this perspective, the use of existing medical registries in combination with a brief questionnaire in the aftermath of disasters is the most promising. Since there is an increasing need for such a tool this approach needs further examination.When disaster strikes it is important to realize that apart from acute health problems that will be addressed by the emergency departments many other problems are likely to occur [1]. Homes may be damaged, sometimes resulting in displacement of the population. Survivors might develop diseases or have other health problems as a consequence of the disaster. These problems may result in health related needs like medical treatment and medication use. Since a disaster might have direct consequences for public health care a clear overview of these health needs is important. Therefore rapid assessment methods are needed to collect reliable, objective information that is immediately required for decision making in the recovery phase of the event. Health care agencies, stakeholders and policy makers will request a rapid insight into health status to take care
Genome-Wide Profiling of p63 DNA–Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus
Evelyn N. Kouwenhoven equal contributor,Simon J. van Heeringen equal contributor,Juan J. Tena equal contributor,Martin Oti,Bas E. Dutilh,M. Eva Alonso,Elisa de la Calle-Mustienes,Leonie Smeenk,Tuula Rinne,Lilian Parsaulian,Emine Bolat,Rasa Jurgelenaite,Martijn A. Huynen,Alexander Hoischen,Joris A. Veltman,Han G. Brunner,Tony Roscioli,Emily Oates,Meredith Wilson,Miguel Manzanares,José Luis Gómez-Skarmeta,Hendrik G. Stunnenberg,Marion Lohrum,Hans van Bokhoven ,Huiqing Zhou
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001065
Abstract: Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA–binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP–seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes.
Heterozygous Mutations of FREM1 Are Associated with an Increased Risk of Isolated Metopic Craniosynostosis in Humans and Mice
Lisenka E. L. M. Vissers equal contributor,Timothy C. Cox equal contributor,A. Murat Maga equal contributor,Kieran M. Short,Fenny Wiradjaja,Irene M. Janssen,Fernanda Jehee,Debora Bertola,Jia Liu,Garima Yagnik,Kiyotoshi Sekiguchi,Daiji Kiyozumi,Hans van Bokhoven,Carlo Marcelis,Michael L. Cunningham,Peter J. Anderson,Simeon A. Boyadjiev,Maria Rita Passos-Bueno,Joris A. Veltman,Ian Smyth,Michael F. Buckley,Tony Roscioli
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002278
Abstract: The premature fusion of the paired frontal bones results in metopic craniosynostosis (MC) and gives rise to the clinical phenotype of trigonocephaly. Deletions of chromosome 9p22.3 are well described as a cause of MC with variably penetrant midface hypoplasia. In order to identify the gene responsible for the trigonocephaly component of the 9p22.3 syndrome, a cohort of 109 patients were assessed by high-resolution arrays and MLPA for copy number variations (CNVs) involving 9p22. Five CNVs involving FREM1, all of which were de novo variants, were identified by array-based analyses. The remaining 104 patients with MC were then subjected to targeted FREM1 gene re-sequencing, which identified 3 further mutant alleles, one of which was de novo. Consistent with a pathogenic role, mouse Frem1 mRNA and protein expression was demonstrated in the metopic suture as well as in the pericranium and dura mater. Micro-computed tomography based analyses of the mouse posterior frontal (PF) suture, the human metopic suture equivalent, revealed advanced fusion in all mice homozygous for either of two different Frem1 mutant alleles, while heterozygotes exhibited variably penetrant PF suture anomalies. Gene dosage-related penetrance of midfacial hypoplasia was also evident in the Frem1 mutants. These data suggest that CNVs and mutations involving FREM1 can be identified in a significant percentage of people with MC with or without midface hypoplasia. Furthermore, we present Frem1 mutant mice as the first bona fide mouse model of human metopic craniosynostosis and a new model for midfacial hypoplasia.
Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice
Joe Rainger,Ellen van Beusekom,Jacqueline K. Ramsay,Lisa McKie,Lihadh Al-Gazali,Rosanna Pallotta,Anita Saponari,Peter Branney,Malcolm Fisher,Harris Morrison,Louise Bicknell,Philippe Gautier,Paul Perry,Kishan Sokhi,David Sexton,Tanya M. Bardakjian,Adele S. Schneider,Nursel Elcioglu,Ferda Ozkinay,Rainer Koenig,Andre Mégarbané,C. Nur Semerci,Ayesha Khan,Saemah Zafar,Raoul Hennekam,Sérgio B. Sousa,Lina Ramos,Livia Garavelli,Andrea Superti Furga,Anita Wischmeijer,Ian J. Jackson,Gabriele Gillessen-Kaesbach,Han G. Brunner,Dagmar Wieczorek,Hans van Bokhoven ,David R. FitzPatrick
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002114
Abstract: Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1tm1a) that reduces mRNA to ~10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1tm1a/tm1a). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1tm1a/tm1a embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
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