558 results on '"Gessler, Manfred"'
Search Results
202. Human CC10, the homologue of rabbit uteroglobin: genomic cloning, chromosomal localization and expression in endometrial cell lines
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Wolf, Markus, primary, Klug, Jörg, additional, Hackenberg, Reinhard, additional, Gessler, Manfred, additional, Grzeschik, Karl-Heinz, additional, Beato, Miguel, additional, and Suske, Guntram, additional
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- 1992
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203. Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1.
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Xiaolin Tu, Jianquan Chen, Joohyun Lim, Karner, Courtney M., Seung-Yon Lee, Heisig, Julia, Wiese, Cornelia, Surendran, Kameswaran, Kopan, Raphael, Gessler, Manfred, and Fanxin Long
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METAZOA ,EMBRYOLOGY ,OSTEOBLASTS ,MESENCHYMAL stem cells ,PHARMACOLOGY - Abstract
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1- mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo. [ABSTRACT FROM AUTHOR]
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- 2012
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204. Characterization of primary wilms tumor cultures as an in vitro model.
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Wegert, Jenny, Bausenwein, Sabrina, Roth, Sabine, Graf, Norbert, Geissinger, Eva, and Gessler, Manfred
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- 2012
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205. Correction: Welter et al. Characteristics of Nephroblastoma/Nephroblastomatosis in Children with a Clinically Reported Underlying Malformation or Cancer Predisposition Syndrome. Cancers 2021, 13 , 5016.
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Welter, Nils, Wagner, Angelo, Furtwängler, Rhoikos, Melchior, Patrick, Kager, Leo, Vokuhl, Christian, Schenk, Jens-Peter, Meier, Clemens Magnus, Siemer, Stefan, Gessler, Manfred, and Graf, Norbert
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NEPHROBLASTOMA ,DISEASE susceptibility ,SYMPTOMS ,CHILDREN - Published
- 2021
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206. Upregulation of Soluble Vascular Endothelial Growth Factor Receptor 1 Contributes to Angiogenesis Defects in the Placenta of α2B-Adrenoceptor-Deficient Mice.
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Muthig, Verena, Gilsbach, Ralf, Haubold, Miriam, Philipp, Melanie, Ivacevic, Tomi, Gessler, Manfred, and Hein, Lutz
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- 2007
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207. Phenotypic variability inHey2 -/-mice and absence ofHEY2mutations in patients with congenital heart defects or Alagille syndrome.
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Fischer, Andreas, Klamt, Barbara, Schumacher, Nina, Glaeser, Christiane, Hansmann, Ingo, Fenge, Hartmut, and Gessler, Manfred
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CONGENITAL heart disease ,GENETIC mutation ,SYNDROMES ,GENETICS ,TETRALOGY of Fallot ,DISEASES - Abstract
The genetic alterations leading to congenital heart defects (CHD) are still poorly understood. We and others have recently shown that in mice loss ofHey2results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases. The phenotype has been postulated to resemble human tetralogy of Fallot. Our analysis of CD1 outbred mice suggests that phenotypic consequences ofHey2loss can be quite variable and dependent on modifier genes as we detected only isolated VSDs with lower prevalence and a significantly reduced mortality rate in this strain. SinceHey2is one of the fewNotchtarget genes, it is also conceivable thatHEY2mutations may account for cases of Alagille syndrome (AGS: variable combinations of heart, skeleton, eye, and facial malformations and cholestasis), in which the typical mutations of theNotchligandJAG1cannot be found. To clarify the role ofHEY2in human CHD and AGS, we screened by direct sequencing 23 children with CHD and 38 patients diagnosed with AGS, which lack mutations in theJAG1gene. We found two types of silent changes in the coding region: a CTT?CTG transition in exon 3 and a CTG?CTC polymorphism in exon 5. Furthermore, a heterozygous SNP in the splice donor site of exon 4 was detected that is unlikely to disrupt splicing. Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation ofHEY2is not a major contributing factor. [ABSTRACT FROM AUTHOR]
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- 2004
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208. Mouse gridlock: No Aortic Coarctation or Deficiency, but Fatal Cardiac Defects in Hey2 −/− Mice
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Gessler, Manfred, Knobeloch, Klaus-Peter, Helisch, Armin, Amann, Kerstin, Schumacher, Nina, Rohde, Elvira, Fischer, Andreas, and Leimeister, Cornelia
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GENETIC mutation , *ZEBRA danio , *MUTAGENESIS - Abstract
Gridlock (grl) is one of the first mutations characterized from the large zebrafish mutagenesis screens, and it results in an arterial (aortic) maturation defect, which was proposed to resemble aortic coarctation, a clinically important human malformation . While the grl mutation appears to be a hypomorph, grl knockdown experiments have shown even stronger effects on arterial development . We have generated a knockout of the murine Hey2 (gridlock) gene to analyze the mammalian phenotype. Surprisingly, Hey2 loss does not affect aortic development, but it instead leads to a massive postnatal cardiac hypertrophy with high lethality during the first 10 days of life. This cardiomyopathy is ameliorated with time in surviving animals that do not appear to be manifestly impaired during adult life. These differences in phenotypes suggest that changes in expression or function of genes during evolution may lead to quite different pathological phenotypes, if impaired. [Copyright &y& Elsevier]
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- 2002
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209. Placental α2-adrenoceptors control vascular development at the interface between mother and embryo.
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Philipp, Melanie, Brede, Marc E., Hadamek, Kerstin, Gessler, Manfred, Lohse, Martin J., and Hein, Lutz
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PREGNANCY complications ,MISCARRIAGE ,PLACENTA ,ADRENALINE ,NORADRENALINE - Abstract
A substantial percentage of human pregnancies are lost as spontaneous abortions after implantation. This is often caused by an inadequately developed placenta. Proper development of the placental vascular system is essential to nutrient and gas exchange between mother and developing embryo. Here we show that α[sub 2]-adrenoceptors, which are activated by adrenaline and noradrenaline, are important regulators of placental structure and function. Mice with deletions in the genes encoding α[sub 2A]-, α[sub 2B]- and α[sub 2c]-adrenoceptors died between embryonic days 9.5 and 11.5 from a severe defect in yolk-sac and placenta development. In wildtype placentae, α[sub 2]-adrenoceptors are abundantly expressed in giant cells, which secrete angiogenic factors to initiate development of the placental vascular labyrinth. In placentae deficient in α[sub 2A]-, α[sub 2B]- and α[sub 2c]-adrenoceptors, the density of fetal blood vessels in the labyrinth was markedly lower than normal, leading to death of the embryos as a result of reduced oxygen and nutrient supply. Basal phosphorylation of the extracellular signal-regulated kinases ERK1 and ERK2 was also lower than normal, suggesting that activation of the mitogen-activated protein kinase (MAP kinase) pathway by α[sub 2]-adrenoceptors is required for placenta and yolk-sac vascular development. Thus, α[sub 2]-adrenoceptors are essential at the placental interface between mother and embryo to establish the circulatory system of the placenta and thus maintain pregnancy. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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210. Characteristics and outcome of synchronous bilateral Wilms tumour in the SIOP WT 2001 Study: Report from the SIOP Renal Tumour Study Group (SIOP-RTSG).
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Sudour-Bonnange, Hélène, van Tinteren, Harm, Ramírez-Villar, Gema L., Godzinski, Jan, Irtan, Sabine, Gessler, Manfred, Chowdhury, Tanzina, Audry, Georges, Fuchs, Joerg, Powis, Mark, van de Ven, Cornelis P., Okoye, Bruce, Smeulders, Naima, Vujanic, Gordan M., Verschuur, Arnaud, L'Herminé-Coulomb, Aurore, de Camargo, Beatriz, de Aguirre Neto, Joaquim Caetano, Schenk, Jens Peter, and van den Heuvel-Eibrink, Mary M.
- Abstract
Background: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma. Methods: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology. Results: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function. Conclusions: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient. Clinical Trial Registration: NCT00047138 [ABSTRACT FROM AUTHOR]
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- 2024
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211. Spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations.
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Sevenet, Nicolas, Lellouch-Tubiana, Arielle, Schofield, Deborah, Hoang-Xuan, Khe, Gessler, Manfred, Birnbaum, Daniel, Jeanpierre, Cecile, Jouvet, Anne, and Delattre, Olivier
- Abstract
Examines the spectrum of hSNF5/INI1 somatic mutations in human cancer and genotype-phenotype correlations. Types of tumor demonstrating hSNF/INI1 mutations; Homozygous deletion of hSNF/INI1 mutations; Functional consequences of somatic mutations in cancer genotype-phenotype correlations.
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- 1999
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212. Analysis of WT1 target gene expression in stably transfected cell lines.
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Thäte, Claudia, Englert, Christoph, and Gessler, Manfred
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NEPHROBLASTOMA ,ZINC-finger proteins ,TUMOR suppressor genes - Abstract
The Wilms' tumour suppressor gene WT1 encodes a zinc finger protein that is mutated in a subset of Wilms' tumours. Mutation screening and animal studies revealed essential roles during development and later function of the kidneys and the entire genitourinary system. Sequence similarity suggested a possible role for WT1 as a transcription factor. Indeed, sequence specific DNA binding and transcriptional activation or repression potential could be demonstrated in transient transfection assays with various reporter constructs. To identify endogenous WT1 target genes we established HEK293 cell lines expressing the different WT1 isoforms in a tetracycline dependent manner. Differential display PCR (ddPCR) was performed on RNA from stable WT1 transfected HEK293 cell lines and two other WT1 transfected lines (G401 and Saos-2). In an extended survey of several thousand ddPCR bands only few differences in intensity were seen and none of these could unambiguously be verified as being WT1 regulated by subsequent Northern blot analysis. In addition, almost none of the WT1 target genes identified to date in transient co-transfection assays could be confirmed by either ddPCR or Northern hybridization in the three stable transfected cell lines. Among the nine genes expressed, the only exceptions were CSF1 and to a lesser extent IGF1R being induced in Saos-2/G401 and HEK293 cells, respectively. At least two of the cell lines tested had previously shown clear biological effects though – either WT1 dependent apoptosis (Saos-2) or greatly reduced tumorigenicity (G401). This suggests that WT1 may regulate only a very small set of genes that escape the detection methods used or it may not act as a transcription factor that influences steady state levels of mRNA. [ABSTRACT FROM AUTHOR]
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- 1998
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213. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.
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Klamt, Barbara, Koziell, Ania, Poulat, Francis, Wieacker, Peter, Scambler, Peter, Berta, Philippe, and Gessler, Manfred
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Studies the cause of Frasier syndrome. Defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms; Phenotype in patients with Denys-Drash syndrome; Characteristic features of Frasier syndrome.
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- 1998
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214. Isolation and characterization of a cosmid contig for the GCPS gene region.
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Vortkamp, Andrea, Heid, Christiane, Gessler, Manfred, and Grzeschik, Karl-Heinz
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The zinc finger gene GLI3 has been shown to be involved in the embryonal development of the limbs and skull. Mutations in GLI3 lead to the development of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutations extra toes (Xt) and anterior digit deformity (add). The GCPS locus on human chromosome 7p13 has recently been isolated in a yeast artifical chromosome (YAC) contig. Here, we describe the establishment of a cosmid contig that was derived from two of the YAC clones, that spans 550 kb of human DNA, and that includes the GLI3 gene. In this contig, three GCPS translocation breakpoints have been mapped to distinct EcoRI fragments in the 3′ half of the gene. In addition, exon-carrying fragments have been identified and the size of the GLI3 gene could be determined as at least 280 kb. The gene is flanked by a CpG island that lies on the 5′ side and that is in close proximity to the first exon detected by the cloned GLI3 cDNA. Further upstream, five segments were found that have been conserved between man and mouse. In the mouse, this region has been characterized as the transgene integration site resulting in the add phenotype. Both the CpG island and the conserved regions are probable candidates for a search for GLI3 promoter and control elements. [ABSTRACT FROM AUTHOR]
- Published
- 1995
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215. A WAGR region gene between PAX-6 and FSHB expressed in fetal brain.
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Schwartz, Faina, Neve, Rachael, Eisenman, Robert, Gessler, Manfred, and Bruns, Gail
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Developmental delay or mental retardation is a frequent component of multi-system anomaly syndromes associated with chromosomal deletions. Isolation of genes involved in the mental dysfunction in these disorders should define loci important in brain formation or function. We have identified a highly conserved locus in the distal part of 11p13 that is prominently expressed in fetal brain. Minimal expression is observed in a number of other fetal tissues. The gene maps distal to PAX-6 but proximal to the loci for brain-derived neurotrophic factor (BDNF) and the beta subunit of follicle stimulating hormone (FSHB), within a region previously implicated in the mental retardation component of some WAGR syndrome patients. Within fetal brain, the corresponding transcript is prominent in frontal, motor and primary visual cortex as well as in the caudate-putamen. The characteristics of this gene, including the striking evolutionary conservation at the locus, suggest that the encoded protein may function in brain development. [ABSTRACT FROM AUTHOR]
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- 1994
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216. Combined Loss of Hey1and HeyLCauses Congenital Heart Defects Because of Impaired Epithelial to Mesenchymal Transition
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Fischer, Andreas, Steidl, Christian, Wagner, Toni U., Lang, Esra, Jakob, Peter M., Friedl, Peter, Knobeloch, Klaus-Peter, and Gessler, Manfred
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Congenital heart defects affect almost 1% of human newborns. Recently, mutations in Notch ligands and receptors have been found to cause a variety of heart defects in rodents and humans. However, the molecular effects downstream of Notch are still poorly understood. Here we report that combined inactivation of Hey1and HeyL, two primary target genes of Notch, causes severe heart malformations, including membranous ventricular septal defects and dysplastic atrioventricular and pulmonary valves. These defects lead to congestive cardiac failure with high lethality. We found both genes to be coexpressed with Notch1, Notch2and the Notch ligand Jagged1in the endocardium of the atrioventricular canal, representing the primary source of mesenchymal cells forming membraneous septum and valves. Atrioventricular explants from Hey1/HeyLdeficient mice exhibited impaired epithelial to mesenchymal transition. Although epithelial to mesenchymal transition was initiated regularly, full transformation into mesenchymal cells failed. This was accompanied by reduced levels of matrix metalloproteinase-2expression and reduced cell density in endocardial cushions in vivo. We further show that loss of Hey2leads to very similar deficiencies, whereas a Notch1null mutation completely abolishes epithelial to mesenchymal transition. Thus, the Heygene family shows overlap in controlling Notch induced endocardial epithelial to mesenchymal transition, a process critical for valve and septum formation.
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- 2007
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217. Expression of mouse dchs1, fjx1, and fat‐jsuggests conservation of the planar cell polarity pathway identified in drosophila
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Rock, Rebecca, Schrauth, Sabrina, and Gessler, Manfred
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The dachsous(ds), fat(ft), and four‐jointed(fj) genes have been identified in Drosophila as part of a signaling pathway that regulates planar cell polarity (PCP). A homologous PCP signaling pathway has also been identified in vertebrates, but nothing is known thus far about the conservation of Ds/Ft/Fj signaling. Here we analyzed and compared for the first time the expression patterns of all ds, ftand fjhomologs in the mouse. During embryogenesis, expression analysis was performed by RNA in situ hybridization and in adult organs by real time PCR. As in Drosophila, we detected a complementary expression of fjx1and dchs1in organs like kidney, lung, and intestine. The ubiquitous expression of ftin several tissues in Drosophila appears to be split into an epithelial expression of fat1/fat3and a mesenchymal expression of fat‐j. These data are compatible with a conservation and subfunctionalization of the Drosophila Ds, Fj, and Fat signaling in higher vertebrates. Developmental Dynamics 234:747–755, 2005. © 2005 Wiley‐Liss, Inc.
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- 2005
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218. Novel Familial WT1Read-Through Mutation Associated With Wilms Tumor and Slow Progressive Nephropathy
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Zirn, Birgit, Wittmann, Stefanie, and Gessler, Manfred
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Wilms tumor gene 1 (WT1) is essential for normal urogenital development. Mutations in WT1are involved in Wilms tumorigenesis and several associated syndromes, such as Denys-Drash, Frasier, or Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome. We report a novel familial WT1point mutation in the stop codon of exon 10 (1730A/G; X450W) in 3 members of 1 family. The index patient is a 22-year-old woman in whom Wilms tumor and ureter duplex were diagnosed at the age of 9 years and who subsequently developed slow progressive nephropathy. Her mother also had late-onset nephropathy that led to end-stage renal failure, whereas renal function in 1 brother of the index patient was not impaired. We hypothesize that this type of mutation (read-through), which leads to an elongated, but otherwise unchanged, WT1protein, may be associated with incomplete penetrance and a relatively late onset of both Wilms tumor and nephropathy in this family.
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- 2005
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219. Identification of BOIP, a novel cDNA highly expressed during spermatogenesis that encodes a protein interacting with the orange domain of the hairy-related transcription factor HRT1/Hey1 in <TOGGLE>Xenopus</TOGGLE> and mouse
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Wayenbergh, Reginald Van, Taelman, Vincent, Pichon, Bruno, Fischer, Andreas, Kricha, Sadia, Gessler, Manfred, Christophe, Daniel, and Bellefroid, Eric J.
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Hairy-related transcription factor (HRT/Hey) genes encode a novel subfamily of basic helix-loop-helix (bHLH) transcription factors related to the Drosophila hairy and Enhancer-of-split (E(spl)) and the mammalian HES proteins that function as downstream mediators of Notch signaling. Using the yeast two-hybrid approach, a previously uncharacterized protein was identified in Xenopus that interacts with XHRT1 (originally referred to as bc8), one member of the HRT/Hey subclass. This protein is evolutionarily conserved in chordates. It binds to sequences adjacent to the bHLH domain of XHRT1 known as the Orange domain and has been named bc8 Orange interacting protein (BOIP). BOIP shows a rather uniform subcellular localization and is recruited to the nucleus upon binding to XHRT1. In Xenopus, XBOIP mRNA is detected by RNase protection analysis throughout embryogenesis. In the adult, the strongest expression is detected in testis. In the mouse, high levels of BOIP mRNA are also found in adult testis. No expression is detected in the embryo and in any of the other adult organs tested. In situ hybridization revealed that BOIP transcripts were detected almost exclusively in round spermatids and that this expression overlaps with that of Hey1 (HRT1), which is expressed throughout spermatogenesis. In view of the importance of the Orange domain for HRT/Hey function, the newly identified BOIP proteins may serve as regulators specifically of HRT1/Hey1 activity. Developmental Dynamics 228:716725, 2003. © 2003 Wiley-Liss, Inc.
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- 2003
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220. Oscillating Expression of c-Hey2in the Presomitic Mesoderm Suggests That the Segmentation Clock May Use Combinatorial Signaling through Multiple Interacting bHLH Factors
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Leimeister, Cornelia, Dale, Kim, Fischer, Andreas, Klamt, Barbara, Hrabe de Angelis, Martin, Radtke, Freddy, McGrew, Michael J, Pourquié, Olivier, and Gessler, Manfred
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Vertebrate somitogenesis comprises the generation of a temporal periodicity, the establishment of anteroposterior compartment identity, and the translation of the temporal periodicity into the metameric pattern of somites. Molecular players at each of these steps are beginning to be identified. Especially, members of the Notch signaling cascade appear to be involved in setting up the somitogenesis clock and subsequent events. We had previously demonstrated specific expression of the mHey1and mHey2basic helix-loop-helix (bHLH) factors during somitogenesis. Here we show that perturbed Notch signaling in Dll1and Notch1knockout mutants affects this expression in the presomitic mesoderm (PSM) and the somites. In the caudal PSM, however, mHey2expression is maintained and thus is likely to be independent of Notch signaling. Furthermore, we analysed the dynamic expression of the respective chicken c-Hey1and c-Hey2genes during somitogenesis. Not only is c-Hey2rhythmically expressed across the chicken presomitic mesoderm like c-hairy1,but its transcription is similarly independent of de novoprotein synthesis. In contrast, the dynamic expression of c-Hey1is restricted to the anterior segmental plate. Both c-Heygenes are coexpressed with c-hairy1in the posterior somite half. Further in vitroand in vivointeraction assays demonstrated direct homo- and heterodimerisation between these hairy-related bHLH proteins, suggesting a combinatorial action in both the generation of a temporal periodicity and the anterior–posterior somite compartmentalisation.
- Published
- 2000
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221. Activation of the Notch pathway in the hair cortex leads to aberrant differentiation of the adjacent hair-shaft layers
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Lin, Meei-Hua, Leimeister, Cornelia, Gessler, Manfred, and Kopan, Raphael
- Abstract
Little is known about the mechanisms underlying the generation of various cell types in the hair follicle. To investigate the role of the Notch pathway in this process, transgenic mice were generated in which an active form of Notch1 (NotchΔE) was overexpressed under the control of the mouse hair keratin A1 (MHKA1) promoter. MHKA-NotchΔE is expressed only in one precursor cell type of the hair follicle, the cortex. Transgenic mice could be easily identified by the phenotypes of curly whiskers and wavy, sheen pelage hair. No effects of activated Notch on proliferation were detected in hair follicles of the transgenic mice. We find that activating Notch signaling in the cortex caused abnormal differentiation of the medulla and the cuticle, two neighboring cell types that did not express activated Notch. We demonstrate that these non-autonomous effects are likely caused by cell-cell interactions between keratinocytes within the hair follicle and that Notch may function in such interactions either by directing the differentiation of follicular cells or assisting cells in interpreting a gradient emanating from the dermal papilla.
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- 2000
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222. Mouse gridlock No Aortic Coarctation or Deficiency, but Fatal Cardiac Defects in Hey2 −/− Mice
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Gessler, Manfred, Knobeloch, Klaus-Peter, Helisch, Armin, Amann, Kerstin, Schumacher, Nina, Rohde, Elvira, Fischer, Andreas, and Leimeister, Cornelia
- Abstract
Gridlock (grl) is one of the first mutations characterized from the large zebrafish mutagenesis screens, and it results in an arterial (aortic) maturation defect, which was proposed to resemble aortic coarctation, a clinically important human malformation [1–3]. While the grl mutation appears to be a hypomorph, grl knockdown experiments have shown even stronger effects on arterial development [4]. We have generated a knockout of the murine Hey2 (gridlock) gene to analyze the mammalian phenotype. Surprisingly, Hey2 loss does not affect aortic development, but it instead leads to a massive postnatal cardiac hypertrophy with high lethality during the first 10 days of life. This cardiomyopathy is ameliorated with time in surviving animals that do not appear to be manifestly impaired during adult life. These differences in phenotypes suggest that changes in expression or function of genes during evolution may lead to quite different pathological phenotypes, if impaired.
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223. Heygenes: a novel subfamily of hairy- and Enhancer of splitrelated genes specifically expressed during mouse embryogenesis
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Leimeister, Cornelia, Externbrink, Alexandra, Klamt, Barbara, and Gessler, Manfred
- Abstract
We have identified a novel subfamily of mammalian hairy/Enhancer of split(E(spl))-related basic helix-loop-helix (bHLH) genes together with a putative Drosophilahomologue. While hairy/E(spl) proteins are characterized by an invariant proline residue in the basic domain and a carboxyterminal groucho-binding WRPW motif, our genes encode a carboxyterminal KPYRPWG sequence and were thus designated as Heygenes (Hairy/E(spl)-related with YRPW motif). Furthermore, they bear a unique C-terminal TE(I/V)GAF motif and the characteristic proline is changed in all Hey family members to glycine. RNA in situ hybridization analysis revealed specific expression of Hey1during development of the nervous system, the somites, the heart and the craniofacial region. Hey2is similarly expressed in the somites whereas it shows a complementary expression in the heart, the craniofacial region and the nervous system. The diversity of expression patterns implies unique functions in neurogenesis, somitogenesis and organogenesis.
- Published
- 1999
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224. Fjx1, the murine homologue of the Drosophila four-jointedgene, codes for a putative secreted protein expressed in restricted domains of the developing and adult brain
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Ashery-Padan, Ruth, Alvarez-Bolado, Gonzalo, Klamt, Barbara, Gessler, Manfred, and Gruss, Peter
- Abstract
The Drosophilagene four jointed(fj) codes for a secreted or cell surface protein important for growth and differentiation of legs and wings and for proper development of the eyes. Here we report the cloning of the mouse four-jointedgene (fjx1) and its pattern of expression in the brain during embryogenesis and in the adult. In the neural plate, fjx1is expressed in the presumptive forebrain and midbrain, and in rhombomere 4, however a small rostral/medial area of the forebrain primordium is devoid of expression. Expression of fjx1in the neural tube can be divided into three phases. (1) In the embryonic brain fjx1is expressed in two patches of neuroepithelium: in the midbrain tectum and the telencephalic vesicles. (2) In fetal and early postnatal brain fjx1is expressed mainly by the primordia of layered telencephalic structures: cortex (ventricular layer and cortical plate), olfactory bulb (subependymal layer and in the mitral cell layer). In addition expression is observed in the superior colliculus. (3) In the adult, fjx1is expressed by neurons evenly distributed in the telencephalon (isocortex, striatum, hippocampus, olfactory bulb, piriform cortex), in the Purkinje cell layer of the cerebellum, and numerous medullary nuclei. In the embryo, strong expression can further be seen in the apical ectodermal ridge of fore- and hindlimbs and in the ectoderm of the branchial arches.
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- 1999
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225. Differential expression of the cellular oncogenes c-src and c-yes in embryonal and adult chicken tissues
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Gessler, Manfred and Barnekow, Angelika
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The cellular onc- genes c-src and c-yes are expressed very differently during chicken embryonic development. The c-src mRNA and its translational product are detectable at high levels in brain extracts of chicken embryos and adult chickens) whereas muscle extracts show an age-dependent decrease in the amounts of c-src-specific mRNA and pp60c-src kinase activity. In contrast) the levels of c-yes mRNA in brain, heart, and muscle are relatively low in early embryonic stages and increase later on to values comparable to those found for liver) while in adult animals the pattern of c-yes expression is similar to that of the c-src gene. From the close correlation between the levels of pp60c-src its enzymatic activity, and its corresponding mRNA at a given stage of development and in given tissues) it appears that the expression of pp60c-src is primarily controlled at the level of transcription. It is suggested that because of the different patterns of expression) the two cellular oncogenes) c-src and c-yes) play different roles in cell proliferation during early embryonic stages as well as in ensuing differentiation processes.
- Published
- 1984
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226. The impact of the route to diagnosis in nephroblastoma.
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Mergen, Marvin, Welter, Nils, Furtwängler, Rhoikos, Melchior, Patrick, Vokuhl, Christian, Gessler, Manfred, Meier, Clemens‐Magnus, Kager, Leo, Schenk, Jens‐Peter, and Graf, Norbert
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NEPHROBLASTOMA , *DIAGNOSIS , *TUMOR diagnosis , *NEOADJUVANT chemotherapy , *RENAL cancer - Abstract
Introduction: Wilms tumor (WT) is the most common childhood kidney cancer. It is a rapid growing embryonal tumor in young children and can be diagnosed with and without tumor related symptoms. Methods: We retrospectively analyzed the route to diagnosis of WT treated prospectively according to the SIOP 93‐01/GPOH and 2001/GPOH in Germany between 1993 and 2022. Four routes were defined: diagnosis due to tumor‐related symptoms, incidental diagnosis during another disease, diagnosis by preventive examinations, and diagnosis within a surveillance program. For these groups we compared clinical and tumor characteristics and outcome. Results: Of 2549 patients with WT 1822 (71.5%) were diagnosed by tumor‐related symptoms, 472 (18.5%) incidentally, 213 (8.4%) by preventive medical examinations, and 42 (1.6%) by surveillance. Age, general health status, tumor volume, and local and overall stage varied significantly between these groups. The youngest patients were those diagnosed by preventive medical examination (mean: 1.70 years). These patients also showed the best general health status. Tumor volume at diagnosis (549 mL) and after preoperative chemotherapy (255 mL) was significantly higher for children with tumor‐related symptoms. The highest percentage of local stage I (78.6%) and the lowest percentage of metastatic disease (4.8%) was found in the surveillance group. The outcome of patients was not significantly different, with up to 19.0% relapses in the surveillance group and 3.0% deaths in the group with tumor‐related symptoms. Conclusion: The route to diagnosis of WT correlates with age, general health status, tumor volume, and stage distribution, but does not impact the outcome of patients. Nonetheless, diagnosis without tumor related symptoms results in lower treatment burden and thus improved quality of life. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
227. A deletion map of the WAGR region on chromosome II
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Gessler, Manfred, Thomas, G. H., Couillin, P., Junien, C., McGillivray, B. C., Hayden, M., Jaschek, G., and Bruns, G. A.
- Subjects
ddc:570 ,Biochemie - Abstract
The WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) region has been assigned to chromosome 11p13 on the basis of overlapping constitutional deletions found in affected individuals. We have utilized 31 DNA probes which map to the WAGR deletion region, together with six reference loci and 13 WAGR-related deletions, to subdivide this area into 16 intervals. Specific intervals have been correlated with phenotypic features, leading to the identification of individual subregions for the aniridia and Wilms tumor loci. Delineation, by specific probes, of multiple intervals above and below the critical region and of five intervals within the overlap area provides a framework map for molecular characterization of WAGR gene loci and of deletion boundary regions.
- Published
- 1989
228. A physical map around the WAGR complex on the short arm of chromosome 11
- Author
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Gessler, Manfred and Bruns, G. A. P.
- Subjects
ddc:570 ,Biochemie - Abstract
A long-range restriction map of part of the short arm of ehromosome 11 including the WAGR region has been constructed using pulsed-field gel electrophoresis and a number of infrequently cutting restriction enzymes. A total of 15.4 Mbp has been mapped in detall, extending from proximal 11p14 to the distal part of 11p12. The map localizes 35 different DNA probes and reveals at least nine areas with features eharaeteristle of BTF islands, some of which may be candidates for the different loci underlying the phenotype of the WAGR syndrome. This map will furthermore allow screening of DNA from individuals with WAGR-related phenotypes and from Wilms tumors for associated chromosomal rearrangements.
- Published
- 1989
229. Cloning of breakpoints of a chromosome translocation identifies the AN2 locus
- Author
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Gessler, Manfred, Simola, Kalle O., and Bruns, Gail A. P.
- Subjects
ddc:610 - Abstract
Chromosome translocations involving llpl3 have been associated with familial aniridia in two kindreds highlighting the chromosomal localization of the AN2 locus. This locus is also part of the WAGR complex (Wilros tumor, aniridia, genitourinary abnormalities, and mental retardation). In one kindred, the translocation is associated with a deletion, and probes for this region were used to identify and clone the breakpoints of the translocation in the second kindred. Comparison of phage restriction maps exclude the presence of any sizable deletion in this case. Sequences at the chromosome 11 breakpoint are conserved in multiple species, suggesting that the translocation falls within the AN2 gene.
- Published
- 1989
230. Molecular mapping and cloning of the breakpoints of a chromosome 11p14.1-p13 deletion associated with the AGR syndrome
- Author
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Gessler, Manfred and Bruns, Gail A. P.
- Subjects
ddc:570 ,Biochemie - Abstract
Chromosome 11p13 is frequently rearranged in individuals with the WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) or parts of this syndrome. To map the cytogenetic aberrations molecularly, we screened DNA from cell Unes with known WAGR-related chromosome abnormalities for rearrangements with pulsed fleld gel (PFG) analysis using probes deleted from one chromosome 11 homolog of a WAGR patient. The first alteration was detected in a cell line from an individual with aniridia, genitourinary anomalies, mental retardation, and a deletion described as 11p14.1-p13. We have located one breakpoint close to probe HU11-164B and we have cloned both breakpoint sites as well as the junctional fragment. The breakpoints subdivide current intervals on the genetic map, and the probes for both sides will serve as important additional markers for a long-range restriction map of this region. Further characterization and sequencing of the breakpoints may yield insight into the mechanisms by which these deletions occur.
- Published
- 1988
231. Deletion of GLI3 supports the homology of the human Greig cephalopolysyndactyly syndrome (GCPS) and the mouse mutant extra toes ( Xt).
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Vortkamp, Andrea, Franz, Thomas, Gessler, Manfred, and Grzeschik, Karl
- Published
- 1992
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232. Six new polymorphic microsatellite markers used for the integration of genetic and physical maps of human chromosome 7.
- Author
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Beck, Simone, Badbanchi, Farah, Otto, Michael, Grzeschik, Nicola, Kunz, Jürgen, Speich, Norbert, Gessler, Manfred, and Grzeschik, Karl-Heinz
- Abstract
We report the isolation and characterization of six new polymorphic dinucleotide repeat microsatellite markers (D7S1491, D7S1492, D7S1493, D7S1494, D7S1495, and D7S 1496), their integration into the genetic map of human chromosome 7 by analysis of 40 CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees, and their use for integration of physical and genetic maps of this chromosome. [ABSTRACT FROM AUTHOR]
- Published
- 1996
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233. Confirmation of the localization of the human recombination activating gene 1 (RAG1) to chromosome 11p13.
- Author
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Schwarz, Klaus, Hameister, Horst, Gessler, Manfred, Grzeschik, Karl-Heinz, Hansen-Hagge, Thomas, and Bartram, Claus
- Abstract
The human recombination activating gene 1 (RAG1) has previously been mapped to chromosomes 14q and 11p. Here we confirm the chromosome 11 assignment by two independent approaches: autoradiographic and fluorescence in situ hybridization to metaphase spreads and analysis of human-hamster somatic cell hybrid DNA by the polymerase chain reaction (PCR) and Southern blotting. Our results unequivocally localize RAG1 to 11p13. [ABSTRACT FROM AUTHOR]
- Published
- 1994
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234. The potassium channel gene HK1 maps to human chromosome 11p14.1, close to the FSHB gene.
- Author
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Gessler, Manfred, Grape, Andrew, Grzeschik, Karl-Heinz, and Pongs, Olaf
- Abstract
Transiently activating (A-type) potassium (K) channels are important regulators of action potential and action potential firing frequencies. HK1 designates the first human cDNA that is highly homologous to the rat RCK4 cDNA that codes for an A-type K-channel. The HK1 channel is expressed in heart. By somatic cell hybrid analysis, the HK1 gene has been assigned to human chromosome 11p13-p14, the WAGR deletion region (Wilms tumor, aniridia, genito-urinary abnormalities and mental retardation). Subsequent pulsed field gel (PFG) analysis and comparison with the well-established PFG map of this region localized the gene to 11p14, 200-600kb telomeric to the FSHB gene. [ABSTRACT FROM AUTHOR]
- Published
- 1992
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235. Identification and Analyses of Extra-Cranial and Cranial Rhabdoid Tumor Molecular Subgroups Reveal Tumors with Cytotoxic T Cell Infiltration
- Author
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Chun, Hye-Jung E., Johann, Pascal D., Milne, Katy, Zapatka, Marc, Buellesbach, Annette, Ishaque, Naveed, Iskar, Murat, Erkek, Serap, Wei, Lisa, Tessier-Cloutier, Basile, Lever, Jake, Titmuss, Emma, Topham, James T., Bowlby, Reanne, Chuah, Eric, Mungall, Karen L., Ma, Yussanne, Mungall, Andrew J., Moore, Richard A., Taylor, Michael D., Gerhard, Daniela S., Jones, Steven J.M., Korshunov, Andrey, Gessler, Manfred, Kerl, Kornelius, Hasselblatt, Martin, Frühwald, Michael C., Perlman, Elizabeth J., Nelson, Brad H., Pfister, Stefan M., Marra, Marco A., and Kool, Marcel
- Abstract
Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are heterogeneous pediatric cancers driven primarily by SMARCB1 loss. To understand the genome-wide molecular relationships between MRTs and ATRTs, we analyze multi-omics data from 140 MRTs and 161 ATRTs. We detect similarities between the MYC subgroup of ATRTs (ATRT-MYC) and extra-cranial MRTs, including global DNA hypomethylation and overexpression of HOXgenes and genes involved in mesenchymal development, distinguishing them from other ATRT subgroups that express neural-like features. We identify five DNA methylation subgroups associated with anatomical sites and SMARCB1mutation patterns. Groups 1, 3, and 4 exhibit cytotoxic T cell infiltration and expression of immune checkpoint regulators, consistent with a potential role for immunotherapy in rhabdoid tumor patients.
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- 2019
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236. The landscape of genomic alterations across childhood cancers
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Gröbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Hans Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, ICGC PedBrain-Seq Project, ICGC MMML-Seq Project, Burkhardt, Birgit, Kratz, Christian P., Witt, Olaf, Van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, Von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Landgraf, Pablo, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Brors, Benedikt, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Schlesner, Matthias, Eils, Roland, Jones, David T. W., Lichter, Peter, Chavez, Lukas, Zapatka, Marc, Pfister, Stefan M., Weber, Ursula, Korshunov, Andrey, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jörg, Von Kalle, Christof, Schmidt, Manfred, Bartholomä, Cynthia, Taylor, Michael, Jones, David, Jäger, Natalie, Korbel, Jan, Stütz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jörg, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Löffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trümper, Lorenz, Zenz, Thorsten, Kube, Dieter, Küppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Möller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, López, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Stadler, Peter F., and Sungalee, Stephanie
- Subjects
3. Good health - Abstract
Nature 555(7696), 321-327 (2018). doi:10.1038/nature25480, Published by Nature Publ. Group, London [u.a.]
237. Genome-Wide Association Analysis Identifies 3 Common Variants Predisposing to Brugada Syndrome, a Rare Disease With High Risk of Sudden Cardiac Death
- Author
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Barc, Julien, Bezzina, Connie, Mizusawa, Yuka, Remme, Carol, Gourraud, Jean-Baptiste, Verkerk, Arie, Peter J. Schwartz, Guicheney, Pascale, Antzelevitch, Charles, Schulze-Bahr, Eric, Behr, Elijah, Tfelt-Hanson, Jacob, Kaab, Stefan, Watanabe, Hiroshi, Horie, Minoru, Makita, Naomasa, Shimizu, Wataru, Froguel, Philippe, Roden, Dan, Christoffels, Vincent, Gessler, Manfred, Wilde, Arthur, Probst, Vincent, Schott, Jean-Jacques, Dina, Christian, and Redon, Richard
238. Epigenetic Characterisation of Uterine Stromal Sarcomas
- Author
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Kommoss, Felix, Kommoss, Friedrich, Schmidt, Dietmar, Lehr, Hans-Anton, Schrimpf, Daniel, Chang, Kenneth, Romero-Perez, Laura, Gruenewald, Thomas, Gessler, Manfred, Pfister, Stefan, Hans-Peter Sinn, Mechtersheimer, Gunhild, Schirmacher, Peter, Deimling, Andreas, and Koelsche, Christian
239. Differential expression of thec-src gene duringIn Vitro differentiation
- Author
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Barnekow, Angelika, primary and Gessler, Manfred, additional
- Published
- 1986
- Full Text
- View/download PDF
240. Cloning of Breakpoints of a Chromosome Translocation Identifies the AN2 Locus
- Author
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Gessler, Manfred, primary, Simola, Kalle O. J., additional, and Bruns, Gail A. P., additional
- Published
- 1989
- Full Text
- View/download PDF
241. Erratum to: Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human.
- Author
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Schmid, Michael, Steinlein, Claus, Tian, Qi, Hanlon Newell, Amy, Gessler, Manfred, Olson, Susan, Rosenwald, Andreas, Kneitz, Burkhard, and Fedorov, Lev
- Published
- 2014
- Full Text
- View/download PDF
242. Author Correction: The landscape of genomic alterations across childhood cancers
- Author
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Gröbner, Susanne, Worst, Barbara, Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa, Johann, Pascal, Balasubramanian, Gnana, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hübschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jürgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas, Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Günther, Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan, Vassal, Gilles, Witt, Hendrik, Burkhardt, Birgit, Kratz, Christian, Witt, Olaf, Tilburg, Cornelis, Kramm, Christof, Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frühwald, Michael, Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Landgraf, Pablo, Koster, Jan, Resnick, Adam, Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela, Zwijnenburg, Danny, Raman, Pichai, Brors, Benedikt, Weber, Ursula, Northcott, Paul, Pajtler, Kristian, Kool, Marcel, Piro, Rosario, Korbel, Jan, Schlesner, Matthias, Eils, Roland, Jones, David, Lichter, Peter, Chavez, Lukas, Zapatka, Marc, and Pfister, Stefan
- Abstract
In this Article, author Benedikt Brors was erroneously associated with affiliation number ‘8’ (Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA); the author’s two other affiliations (affiliations ‘3’ and ‘7’, both at the German Cancer Research Center (DKFZ)) were correct. This has been corrected online.
- Published
- 2018
- Full Text
- View/download PDF
243. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels
- Author
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Hupe, Mike, Li, Minerva Xueting, Kneitz, Susanne, Davydova, Daria, Yokota, Chika, Kele, Julianna, Hot, Belma, Stenman, Jan M., and Gessler, Manfred
- Abstract
Gene expression profiling identifies transcription factors involved in maturation of the blood-brain barrier.
- Published
- 2017
- Full Text
- View/download PDF
244. Differential expression of the c-src gene during In Vitro differentiation.
- Author
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Barnekow, Angelika and Gessler, Manfred
- Published
- 1986
- Full Text
- View/download PDF
245. Differential expression of thec-srcgene duringInVitrodifferentiation
- Author
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Barnekow, Angelika and Gessler, Manfred
- Published
- 1986
- Full Text
- View/download PDF
246. DGCR8 E518K mutation found in Wilms tumors leads to a partial miRNA processing defect that alters gene expression patterns and biological processes.
- Author
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Vardapour, Romina, Kehl, Tim, Kneitz, Susanne, Ludwig, Nicole, Meese, Eckart, Lenhof, Hans-Peter, and Gessler, Manfred
- Subjects
- *
NEPHROBLASTOMA , *GENE expression , *MICRORNA , *EMBRYONIC stem cells , *EPIBLAST - Abstract
Wilms tumor (WT) is the most common renal tumor in childhood. We and others have previously identified oncogenic driver mutations affecting the microprocessor genes DROSHA and DGCR8 that lead to altered miRNA expression patterns. In the case of DGCR8 , a single recurrent hotspot mutation (E518K) was found in the RNA binding domain. To functionally assess this mutation in vitro , we generated mouse Dgcr8 -KO embryonic stem cell (mESC) lines with an inducible expression of wild-type or mutant DGCR8 , mirroring the hemizygous mutant expression seen in WT. RNA-seq analysis revealed significant differences of miRNA expression profiles in DGCR8-E518K compared with DGCR8-wild-type mESCs. The E518K mutation only led to a partial rescue of the reported miRNA processing defect in Dgcr8 -KO, with selectively reduced expression of numerous canonical miRNAs. Nevertheless, DGCR8-E518K retained significant activity given its ability to still process many miRNAs. Subsequent to altered miRNA levels, the expression of mRNA targets was likewise changed. Functional assays showed that DGCR8-E518K cells still have a partial proliferation and differentiation defect but were able to rescue critical biological processes in embryoid body development. The stem cell program could be shut down and all three germ layers were formed. These findings suggest that the E518K mutation leads to a partial reduction of microprocessor activity and altered specificity with selective impairment only in certain developmental contexts, apparently including nephrogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
247. Hey bHLH Factors in Cardiovascular Development.
- Author
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Wiese, Cornelia, Heisig, Julia, and Gessler, Manfred
- Subjects
- *
CARDIOVASCULAR system , *HEART cells , *PHENOTYPES , *LABORATORY mice , *EPITHELIAL cells - Abstract
The Notch pathway is now firmly established as a key signaling system for embryonic cardiovascular development as well as some adult pathologies in vertebrates. We have identified Hey bHLH transcriptional repressors as critical, but partly redundant transducers of these signals. Hey proteins control cardiomyocyte differentiation, epithelial to mesenchymal transition of endocardial cells, and a number of key features of arterial endothelial cells with corresponding defects in knockout mice. While most of the phenotypes are described in embryonic development, there is increasing evidence for additional adult pathologies. Despite the functional importance of Hey proteins little is still known about their molecular targets and interactions. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
248. The rodent Four-jointed ortholog Fjx1 regulates dendrite extension
- Author
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Probst, Barbara, Rock, Rebecca, Gessler, Manfred, Vortkamp, Andrea, and Püschel, Andreas W.
- Subjects
- *
NEURONS , *NERVOUS system , *GENOTYPE-environment interaction , *CELLS - Abstract
Abstract: The extrinsic and intrinsic factors that regulate the size and complexity of dendritic arborizations are still poorly understood. Here we identify Fjx1, the rodent ortholog of the Drososphila planar cell polarity (PCP) protein Four-jointed (Fj), as a new inhibitory factor that regulates dendrite extension. The Drosophila gene four-jointed (fj) has been suggested to provide directional information in wing discs, but the mechanism how it acts is only poorly understood and the function of its mammalian homolog Fjx1 remains to be investigated. We analyzed the phenotype of a null mutation for mouse Fjx1. Homozygous Fjx1 mutants show an abnormal morphology of dendritic arbors in the hippocampus. In cultured hippocampal neurons from Fjx1 mutant mice, loss of Fjx1 resulted in an increase in dendrite extension and branching. Addition of Fjx1 to cultures of dissociated hippocampal neurons had the opposite effect and reduced the length of dendrites and decreased dendritic branching. Rescue experiments with cultured neurons showed that Fjx1 can act both cell-autonomously and non-autonomously. Our results identify Fjx1 as a new inhibitory factor that regulates dendrite extension. [Copyright &y& Elsevier]
- Published
- 2007
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249. MYCN and MAX alterations in Wilms tumor and identification of novel N-MYC interaction partners as biomarker candidates.
- Author
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Jiménez Martín, Ovidio, Schlosser, Andreas, Furtwängler, Rhoikos, Wegert, Jenny, and Gessler, Manfred
- Subjects
- *
NEPHROBLASTOMA , *BIOMARKERS , *MUTANT proteins , *PROTEIN stability , *TRANSCRIPTION factors , *ADULT child abuse victims , *CANCER patients - Abstract
Background: Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized. Methods: We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes. Results: Mutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential. Conclusions: The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
250. Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations.
- Author
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Koelsche, Christian, Mynarek, Martin, Schrimpf, Daniel, Bertero, Luca, Serrano, Jonathan, Sahm, Felix, Reuss, David E., Hou, Yanghao, Baumhoer, Daniel, Vokuhl, Christian, Flucke, Uta, Petersen, Iver, Brück, Wolfgang, Rutkowski, Stefan, Zambrano, Sandro Casavilca, Garcia Leon, Juan Luis, Diaz Coronado, Rosdali Yesenia, Gessler, Manfred, Tirado, Oscar M., and Mora, Jaume
- Subjects
- *
PLEUROPULMONARY blastomas , *RHABDOMYOSARCOMA , *SARCOMA - Abstract
Patients with DICER1 predisposition syndrome have an increased risk to develop pleuropulmonary blastoma, cystic nephroma, embryonal rhabdomyosarcoma, and several other rare tumor entities. In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature of DICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurring TP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots of KRAS (8/22; 36%) and mutations or deletions of NF1 (7/22; 32%), followed by mutations of FGFR4 (2/22; 9%), NRAS (2/22; 9%), and amplification of EGFR (1/22; 5%). A germline DICER1 mutation was detected in two of five cases with constitutional DNA available. Notably, none of the patients showed evidence of a cancer-related syndrome at the time of diagnosis. In contrast to the genetic findings, the morphological features of these tumors were less distinctive, although rhabdomyoblasts or rhabdomyoblast-like cells could retrospectively be detected in all cases. The identified combination of genetic events indicates a relationship between the intracranial tumors analyzed and DICER1 predisposition syndrome-associated sarcomas such as embryonal rhabdomyosarcoma or the recently described group of anaplastic sarcomas of the kidney. However, the intracranial tumors in our series were initially interpreted to represent various tumor types, but rhabdomyosarcoma was not among the typical differential diagnoses considered. Given the rarity of intracranial sarcomas, this molecularly clearly defined group comprises a considerable fraction thereof. We therefore propose the designation “spindle cell sarcoma with rhabdomyosarcoma-like features, DICER1 mutant” for this intriguing group. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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