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Search Results: 1 - 10 of 186257 matches for " Gert Jan B. van Ommen "
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Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy
Annemieke Aartsma-Rus, Anneke AM Janson, Gert-Jan B van Ommen, Judith CT van Deutekom
BMC Medical Genetics , 2007, DOI: 10.1186/1471-2350-8-43
Abstract: Cultured muscle cells from DMD patients carrying duplications were transfected with AONs targeting the duplicated exons, and the dystrophin RNA and protein were analyzed.For two brothers with an exon 44 duplication, skipping was, even at suboptimal transfection conditions, so efficient that both exons 44 were skipped, thus generating, once more, an out-of-frame transcript. In such cases, one may resort to multi-exon skipping to restore the reading frame, as is shown here by inducing skipping of exon 43 and both exons 44. By contrast, in cells from a patient with an exon 45 duplication we were able to induce single exon 45 skipping, which allowed restoration of wild type dystrophin. The correction of a larger duplication (involving exons 52 to 62), by combinations of AONs targeting the outer exons, appeared problematic due to inefficient skipping and mistargeting of original instead of duplicated exons.The correction of DMD duplications by exon skipping depends on the specific exons targeted. Its options vary from the ideal one, restoring for the first time the true, wild type dystrophin, to requiring more 'classical' skipping strategies, while the correction of multi-exon deletions may need the design of tailored approaches.Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are allelic disorders caused by mutations in the DMD gene, which codes for dystrophin [1,2]. Duchenne patients are diagnosed at a young age, suffer from rapid and progressive loss of muscle function and mostly die before the age of 30 due to respiratory or heart failure [3]. By contrast, Becker patients are diagnosed at a later age, often remain ambulant until later in life and generally have near normal life expectancies, although more severe cases are known as well [3]. This discrepancy can be explained by the type of mutation: out-of-frame mutations lead to prematurely truncated, non-functional dystrophin proteins and are associated with the severe DMD phenotype, whereas in-fra
GeneHopper: a web-based search engine to link gene-expression platforms through GenBank accession numbers
B Anders T Svensson, Arja J Kreeft, Gert-Jan B van Ommen, Johan T den Dunnen, Judith M Boer
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-5-r35
Abstract: Genome-wide analysis of gene expression provides insight into the transcriptional state of a cell or tissue sample, measuring RNA levels for thousands of genes in parallel. Among the most commonly applied technologies are photolithographically synthesized oligonucleotide chips [1], printed microarrays using cDNA probes or oligonucleotides [2-5], and serial analysis of gene expression (SAGE) [6]. Array-based technologies measure hybridization signal intensities in one or two channels for each array feature or probe, resulting in absolute or relative information about the expression levels of the corresponding transcripts in the samples. Array probes are produced by polymerase chain reaction (PCR) amplification of selected cDNAs or designed on the basis of cDNA or gene sequence information. SAGE results in quantitative information connected to 10-14 base-pair (bp) sequence tags derived from the 3' ends of transcripts.Expressed sequence tag (EST) sequencing projects have generated millions of cDNA sequences for human, mouse and other organisms that are identified by an accession number in databases such as GenBank. To group these individual sequence reads into sets representing one transcript, several efforts to cluster the ESTs were developed [7-9]. UniGene, developed at the National Center for Biotechnology Information (NCBI) [10], automatically clusters ESTs derived from one organism on the basis of sequence homology, generating a nonredundant set of clusters representing (parts of) transcripts [7]. As GenBank is growing, the clustering is carried out regularly, resulting in new so-called UniGene builds. A number of commercial cDNA clone libraries and commercial chip formats are based on UniGene clusters (including [11,12]). In general, a sequence-specific identifier (GenBank accession number) serves as a reference to the array probe sequence. Likewise, SAGE tags, which are unique for each transcript, are mapped to UniGene clusters and GenBank accession numbers [13,
Integrated analysis of DNA copy number and gene expression microarray data using gene sets
Renée X Menezes, Marten Boetzer, Melle Sieswerda, Gert-Jan B van Ommen, Judith M Boer
BMC Bioinformatics , 2009, DOI: 10.1186/1471-2105-10-203
Abstract: We propose to analyse copy number and expression array data using gene sets, rather than individual genes. The proposed model is robust and sensitive. We re-analysed two publicly available datasets as illustration. These two independent breast cancer datasets yielded similar patterns of association between gene dosage and gene expression levels, in spite of different platforms having been used. Our comparisons show a clear advantage to using sets of genes' expressions to detect associations with long-spanning, low-amplitude copy number aberrations. In addition, our model allows for using additional explanatory variables and does not require mapping between copy number and expression probes.We developed a general and flexible tool for integration of multiple microarray data sets, and showed how the identification of genes whose expression is affected by copy number aberrations provides a powerful approach to prioritize putative targets for functional validation.Tumor cells accumulate genetic damage, including changes in DNA copy number, sequence and methylation, resulting in the dysfunctioning of key regulators [1]. The advent of microarray technology has allowed genome-wide monitoring of these molecular changes at the DNA and RNA level. Gene expression profiling has facilitated classification of cancers into biologically and clinically distinct categories [2-7]. High-resolution array-based comparative genomic hybridization (array-CGH) has allowed the delineation of recurrent DNA copy number alterations in tumors [8-10]. Gene dosage changes play an important role in tumor development; oncogenes may be enhanced by DNA amplification and tumor suppressor genes may be inactivated by a physical deletion. Therefore, integrated analysis of both copy number and gene expression microarray data could give additional information about the role of copy number alterations in the development of cancer.Combined analysis of DNA copy number and gene expression microarrays of the same
Assessment of the feasibility of exon 45–55 multiexon skipping for duchenne muscular dystrophy
Laura van Vliet, Christa L de Winter, Judith CT van Deutekom, Gert-Jan B van Ommen, Annemieke Aartsma-Rus
BMC Medical Genetics , 2008, DOI: 10.1186/1471-2350-9-105
Abstract: We here tested the feasibility of inducing multiexon 45–55 in control and patient muscle cell cultures using various AON cocktails.In all experiments, the exon 45–55 skip frequencies were minimal and comparable to those observed in untreated cells.We conclude that current state of the art does not sufficiently support clinical development of multiexon skipping for DMD.Antisense-mediated exon skipping is emerging as a very promising therapeutic approach for Duchenne muscular dystrophy (DMD) [1]. The aim of this approach is to restore the disrupted reading frame of DMD transcripts, and allow synthesis of partly functional, internally deleted Becker-like dystrophins, rather than prematurely truncated non-functional Duchenne dystrophins. This can be achieved by antisense oligonucleotides (AONs) that target specific exons and hide them from the splicing machinery during pre-mRNA splicing, resulting in the skipping of said exons [2]. Proof of concept of this strategy has been obtained in numerous patient-derived cell cultures with different types of mutations, the mdx mouse model and recently in a first clinical trial where AONs were injected locally in the tibialis anterior muscle of 4 Duchenne patients [1,3-9]. One of the disadvantages of this therapy is its mutation specificity: different exons have to be skipped to restore the reading frame for different mutations [10]. Fortunately, most mutations involve deletions of one or more exons between exon 45 and 53 or between exon 2–20 (50% and 15% of all mutations, respectively) [11]. Therefore, restoration of the reading frame for over 50% of all patients (75% of deletion patients) is theoretically feasible using a strategically selected set of only 10 exons [12]. Skipping of exon 51 is beneficial for the largest group of patients (19% of all deletions, or 13% of all Duchenne patients, (Aartsma-Rus et al. accepted manuscript).Nevertheless, it would be more straightforward if a single formulation of AONs would be applicable
Literature-aided meta-analysis of microarray data: a compendium study on muscle development and disease
Rob Jelier, Peter AC 't Hoen, Ellen Sterrenburg, Johan T den Dunnen, Gert-Jan B van Ommen, Jan A Kors, Barend Mons
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-291
Abstract: While the overlap in both genes and overrepresented GO-terms was poor, LAMA retrieved many more biologically meaningful links between studies, with substantially lower influence of technical factors. LAMA correctly grouped muscular dystrophy, regeneration and myositis studies, and linked patient and corresponding mouse model studies. LAMA also retrieves the connecting biological concepts. Among other new discoveries, we associated cullin proteins, a class of ubiquitinylation proteins, with genes down-regulated during muscle regeneration, whereas ubiquitinylation was previously reported to be activated during the inverse process: muscle atrophy.Our literature-based association analysis is capable of finding hidden common biological denominators in microarray studies, and circumvents the need for raw data analysis or curated gene annotation databases.The comparative analysis of expression microarray studies can refine conclusions and interpretations from individual studies and can be used to identify previously uncharacterized parallels between studies [1,2]. However, such analyses are hampered by the large influences of biological variation between specimens (see e.g. Eid-Dor et al. [3]), and technical differences between the studies [4-9] on the identified differentially expressed genes. The varying technical factors include: differences in experimental procedures for the collection of the biological material and for RNA amplification and labeling [8], differences in sampling times and the DNA microarray platform used (see Kuo et al. [9] for a recent platform comparison), and the applied statistical analysis [6].To overcome this hurdle, it has been suggested that studies should be compared at the level of perturbed biological processes [10,11]. This could be more robust as different genes may hint at the same process. To identify perturbed biological processes, methodologies have been developed in recent years by analysis of the correlated behaviour of groups of gen
Interspecies Translation of Disease Networks Increases Robustness and Predictive Accuracy
Seyed Yahya Anvar ,Allan Tucker,Veronica Vinciotti,Andrea Venema,Gert-Jan B. van Ommen,Silvere M. van der Maarel,Vered Raz,Peter A. C. ‘t Hoen
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1002258
Abstract: Gene regulatory networks give important insights into the mechanisms underlying physiology and pathophysiology. The derivation of gene regulatory networks from high-throughput expression data via machine learning strategies is problematic as the reliability of these models is often compromised by limited and highly variable samples, heterogeneity in transcript isoforms, noise, and other artifacts. Here, we develop a novel algorithm, dubbed Dandelion, in which we construct and train intraspecies Bayesian networks that are translated and assessed on independent test sets from other species in a reiterative procedure. The interspecies disease networks are subjected to multi-layers of analysis and evaluation, leading to the identification of the most consistent relationships within the network structure. In this study, we demonstrate the performance of our algorithms on datasets from animal models of oculopharyngeal muscular dystrophy (OPMD) and patient materials. We show that the interspecies network of genes coding for the proteasome provide highly accurate predictions on gene expression levels and disease phenotype. Moreover, the cross-species translation increases the stability and robustness of these networks. Unlike existing modeling approaches, our algorithms do not require assumptions on notoriously difficult one-to-one mapping of protein orthologues or alternative transcripts and can deal with missing data. We show that the identified key components of the OPMD disease network can be confirmed in an unseen and independent disease model. This study presents a state-of-the-art strategy in constructing interspecies disease networks that provide crucial information on regulatory relationships among genes, leading to better understanding of the disease molecular mechanisms.
Human Papillomavirus Deregulates the Response of a Cellular Network Comprising of Chemotactic and Proinflammatory Genes
Rezaul Karim,Craig Meyers,Claude Backendorf,Kristina Ludigs,Rienk Offringa,Gert-Jan B. van Ommen,Cornelis J. M. Melief,Sjoerd H. van der Burg,Judith M. Boer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017848
Abstract: Despite the presence of intracellular pathogen recognition receptors that allow infected cells to attract the immune system, undifferentiated keratinocytes (KCs) are the main targets for latent infection with high-risk human papilloma viruses (hrHPVs). HPV infections are transient but on average last for more than one year suggesting that HPV has developed means to evade host immunity. To understand how HPV persists, we studied the innate immune response of undifferentiated human KCs harboring episomal copies of HPV16 and 18 by genome-wide expression profiling. Our data showed that the expression of the different virus-sensing receptors was not affected by the presence of HPV. Poly(I:C) stimulation of the viral RNA receptors TLR3, PKR, MDA5 and RIG-I, the latter of which indirectly senses viral DNA through non-self RNA polymerase III transcripts, showed dampening in downstream signalling of these receptors by HPVs. Many of the genes downregulated in HPV-positive KCs involved components of the antigen presenting pathway, the inflammasome, the production of antivirals, pro-inflammatory and chemotactic cytokines, and components downstream of activated pathogen receptors. Notably, gene and/or protein interaction analysis revealed the downregulation of a network of genes that was strongly interconnected by IL-1β, a crucial cytokine to activate adaptive immunity. In summary, our comprehensive expression profiling approach revealed that HPV16 and 18 coordinate a broad deregulation of the keratinocyte's inflammatory response, and contributes to the understanding of virus persistence.
CORE_TF: a user-friendly interface to identify evolutionary conserved transcription factor binding sites in sets of co-regulated genes
Matthew S Hestand, Michiel van Galen, Michel P Villerius, Gert-Jan B van Ommen, Johan T den Dunnen, Peter AC 't Hoen
BMC Bioinformatics , 2008, DOI: 10.1186/1471-2105-9-495
Abstract: We have developed a novel tool, "CORE_TF" (Conserved and Over-REpresented Transcription Factor binding sites) that identifies common transcription factor binding sites in promoters of co-regulated genes. To improve upon existing binding site predictions, the tool searches for position weight matrices from the TRANSFACR database that are over-represented in an experimental set compared to a random set of promoters and identifies cross-species conservation of the predicted transcription factor binding sites. The algorithm has been evaluated with expression and chromatin-immunoprecipitation on microarray data. We also implement and demonstrate the importance of matching the random set of promoters to the experimental promoters by GC content, which is a unique feature of our tool.The program CORE_TF is accessible in a user friendly web interface at http://www.LGTC.nl/CORE_TF webcite. It provides a table of over-represented transcription factor binding sites in the users input genes' promoters and a graphical view of evolutionary conserved transcription factor binding sites. In our test data sets it successfully predicts target transcription factors and their binding sites.There are both experimental and computational approaches to identify transcription factors (TF) and their relevant binding sites. In the wet lab, hypothesis driven techniques, such as deletion constructs with luciferase reporter assays and chromatin-immunoprecipitation on microarrays (ChIP-on-chip), can be used to identify TF binding site (TFBS) regions. Luciferase assays can prove that a specific region has regulatory function, but is laborious and time consuming. ChIP-on-chip is more global, but requires prior knowledge of which TF to target using a specific antibody and is laborious, time consuming, and expensive. Faster and cheaper in silico methods have been in development which can identify potential TF and their binding sites. They also tend to target more precise the TFBS instead of just contai
Cost-effective HRMA pre-sequence typing of clone libraries; application to phage display selection
Barry A Pepers, Menno H Schut, Rolf HAM Vossen, Gert-Jan B van Ommen, Johan T den Dunnen, Willeke MC van Roon-Mom
BMC Biotechnology , 2009, DOI: 10.1186/1472-6750-9-50
Abstract: HRMA results nicely matched those obtained with ELISA and compared favourably to DNA fingerprinting of restriction digested clone insert-PCR. DNA sequence analysis confirmed that HRMA-clustered clones contained identical inserts.Using HRMA, analysis of up to 384 samples can be done simultaneously and will take approximately 30 minutes. Clustering of clones can be largely automated using the system's software within 2 hours. Applied to the analysis of clones obtained after phage display antibody selection, HRMA facilitated a quick overview of the overall success as well as the identification of identical clones. Our approach can be used to characterize any clone set prior to sequencing, thereby reducing sequencing costs significantly.Phage display libraries consist of small antibody fragments cloned into a display phage vector, allowing efficient antibody screening and production in a bacterial system [1,2]. Traditional antibodies are composed of a heavy- and a light-chain that need to recombine in a tetramer for the formation of a functional antibody. Because most of these random recombinations will yield non-functional antibodies, when produced as recombinant fragments in E. coli, isolation of effective antibodies demands extremely large phage libraries. Camelidae have, next to conventional antibodies, dimeric heavy chain antibodies (HCAb) that lack light chains [3]. The variable domain of the HCAb (VHH) has a single binding domain with a specificity and affinity similar to conventional antibodies [4,5]. In a phage display library, each phage displays a different antigen-binding domain on its surface. To isolate specific antibodies, phage particles from a library are bound to an antigen, recovered and used to infect fresh bacteria. Subsequently, phages go through several rounds of epitope binding and re-infection resulting in an enrichment of binding phages. A perfect experiment will ultimately yield groups of phages, each encoding a different antibody directed aga
Deregulation of the ubiquitin-proteasome system is the predominant molecular pathology in OPMD animal models and patients
Seyed Anvar, Peter AC 't Hoen, Andrea Venema, Barbara van der Sluijs, Baziel van Engelen, Marc Snoeck, John Vissing, Capucine Trollet, George Dickson, Aymeric Chartier, Martine Simonelig, Gert-Jan B van Ommen, Silvere M van der Maarel, Vered Raz
Skeletal Muscle , 2011, DOI: 10.1186/2044-5040-1-15
Abstract: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset progressive muscle disorder for which the underlying molecular mechanisms are largely unknown. This autosomal dominant muscular dystrophy has an estimated prevalence of 1 in 100,000 worldwide [1]. A higher prevalence has been reported in the Jewish Caucasian and French-Canadian populations (1 in 600 and 1 in 1,000, respectively) [2,3]. OPMD is caused by expansion of a homopolymeric alanine (Ala) stretch at the N-terminus of the Poly(A) Binding Protein Nuclear 1 (PABPN1) by two to seven additional Ala residues [4]. Although PABPN1 is ubiquitously expressed, the clinical and pathological features of OPMD are restricted to a subset of skeletal muscles, causing progressive ptosis, dysphagia, and limb muscle weakness. In affected muscles, the expanded PABPN1 (expPABPN1) accumulates in intranuclear inclusions (INI) [5]. Animal models for OPMD were generated in Drosophila, mice and Caenorhabditis elegans with a muscle-specific expression of expPABPN1 [6-8]. These models recapitulate INI formation and progressive muscle weakness in OPMD, and a correlation between INI formation and muscle weakness has been reported [6-8]. In these OPMD models protein disaggregation approaches attenuate muscle symptoms [8-10]. So far, however, the molecular mechanisms that are associated with OPMD onset and progression are not known. Previously, we performed transcriptome analysis on skeletal muscles from a mouse model of OPMD and found massive gene deregulation, which was reflected by a broad spectrum of altered cellular pathways [11]. We found an association of transcriptional changes with muscle atrophy [11]. Muscle atrophy was recently reported in homozygous OPMD patients [2]. However, the vast majority of OPMD patients are heterozygous and muscle atrophy is not a common pathological characteristic of the disease in its early stages. Importantly, a mouse model with low and constitutive expPABPN1 expression exhibits minor muscle def
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