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Stefan mundlos

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https://www.readbyqxmd.com/read/29662163/polymer-physics-predicts-the-effects-of-structural-variants-on-chromatin-architecture
#1
Simona Bianco, Darío G Lupiáñez, Andrea M Chiariello, Carlo Annunziatella, Katerina Kraft, Robert Schöpflin, Lars Wittler, Guillaume Andrey, Martin Vingron, Ana Pombo, Stefan Mundlos, Mario Nicodemi
Structural variants (SVs) can result in changes in gene expression due to abnormal chromatin folding and cause disease. However, the prediction of such effects remains a challenge. Here we present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer-promoter contacts. PRISMR predicts higher-order chromatin structure from genome-wide chromosome conformation capture (Hi-C) data. Using the EPHA4 locus as a model, the effects of pathogenic SVs are predicted in silico and compared to Hi-C data generated from mouse limb buds and patient-derived fibroblasts...
April 16, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29653293/transcriptional-profiling-of-murine-osteoblast-differentiation-based-on-rna-seq-expression-analyses
#2
Layal Abo Khayal, Johannes Grünhagen, Ivo Provazník, Stefan Mundlos, Uwe Kornak, Peter N Robinson, Claus-Eric Ott
Osteoblastic differentiation is a multistep process characterized by osteogenic induction of mesenchymal stem cells, which then differentiate into proliferative pre-osteoblasts that produce copious amounts of extracellular matrix, followed by stiffening of the extracellular matrix, and matrix mineralization by hydroxylapatite deposition. Although these processes have been well characterized biologically, a detailed transcriptional analysis of murine primary calvaria osteoblast differentiation based on RNA sequencing (RNA-seq) analyses has not previously been reported...
April 10, 2018: Bone
https://www.readbyqxmd.com/read/29623569/advances-in-computer-assisted-syndrome-recognition-by-the-example-of-inborn-errors-of-metabolism
#3
Jean T Pantel, Max Zhao, Martin A Mensah, Nurulhuda Hajjir, Tzung-Chien Hsieh, Yair Hanani, Nicole Fleischer, Tom Kamphans, Stefan Mundlos, Yaron Gurovich, Peter M Krawitz
Significant improvements in automated image analysis have been achieved in recent years and tools are now increasingly being used in computer-assisted syndromology. However, the ability to recognize a syndromic facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult. For a systematic analysis of these influencing factors we chose the lysosomal storage diseases mucolipidosis as well as mucopolysaccharidosis type I and II that are known for their wide and overlapping phenotypic spectra...
April 5, 2018: Journal of Inherited Metabolic Disease
https://www.readbyqxmd.com/read/29561836/impaired-proteoglycan-glycosylation-elevated-tgf-%C3%AE-signaling-and-abnormal-osteoblast-differentiation-as-the-basis-for-bone-fragility-in-a-mouse-model-for-gerodermia-osteodysplastica
#4
Wing Lee Chan, Magdalena Steiner, Tomasz Witkos, Johannes Egerer, Björn Busse, Shuji Mizumoto, Jan M Pestka, Haikuo Zhang, Ingrid Hausser, Layal Abo Khayal, Claus-Eric Ott, Mateusz Kolanczyk, Bettina Willie, Thorsten Schinke, Chiara Paganini, Antonio Rossi, Kazuyuki Sugahara, Michael Amling, Petra Knaus, Danny Chan, Martin Lowe, Stefan Mundlos, Uwe Kornak
Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis. GORAB, the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the GorabNull full knockout, Gorab was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only GorabPrx1 and GorabRunx2 mutants showed dramatically thinned, porous cortical bone and spontaneous fractures...
March 21, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29493576/response-to-peron-et-al
#5
Bjørt K Kragesteen, Denis Duboule, Stefan Mundlos, Malte Spielmann
No abstract text is available yet for this article.
March 1, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29341480/cutis-laxa-and-excessive-bone-growth-due-to-de-novo-mutations-in-ptdss1
#6
Juliette Piard, James Lespinasse, Marketa Vlckova, Martin A Mensah, Sorin Iurian, Martina Simandlova, Marcela Malikova, Oliver Bartsch, Massimiliano Rossi, Marion Lenoir, Frédérique Nugues, Stefan Mundlos, Uwe Kornak, Philip Stanier, Sérgio B Sousa, Lionel Van Maldergem
The cutis laxa syndromes are multisystem disorders that share loose redundant inelastic and wrinkled skin as a common hallmark clinical feature. The underlying molecular defects are heterogeneous and 13 different genes have been involved until now, all of them being implicated in elastic fiber assembly. We provide here molecular and clinical characterization of three unrelated patients with a very rare phenotype associating cutis laxa, facial dysmorphism, severe growth retardation, hyperostotic skeletal dysplasia, and intellectual disability...
January 17, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29310717/characterization-of-glycosylphosphatidylinositol-biosynthesis-defects-by-clinical-features-flow-cytometry-and-automated-image-analysis
#7
Alexej Knaus, Jean Tori Pantel, Manuela Pendziwiat, Nurulhuda Hajjir, Max Zhao, Tzung-Chien Hsieh, Max Schubach, Yaron Gurovich, Nicole Fleischer, Marten Jäger, Sebastian Köhler, Hiltrud Muhle, Christian Korff, Rikke S Møller, Allan Bayat, Patrick Calvas, Nicolas Chassaing, Hannah Warren, Steven Skinner, Raymond Louie, Christina Evers, Marc Bohn, Hans-Jürgen Christen, Myrthe van den Born, Ewa Obersztyn, Agnieszka Charzewska, Milda Endziniene, Fanny Kortüm, Natasha Brown, Peter N Robinson, Helenius J Schelhaas, Yvonne Weber, Ingo Helbig, Stefan Mundlos, Denise Horn, Peter M Krawitz
BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS)...
January 9, 2018: Genome Medicine
https://www.readbyqxmd.com/read/29236091/noncoding-copy-number-variations-are-associated-with-congenital-limb-malformation
#8
Ricarda Flöttmann, Bjørt K Kragesteen, Sinje Geuer, Magdalena Socha, Lila Allou, Anna Sowińska-Seidler, Laure Bosquillon de Jarcy, Johannes Wagner, Aleksander Jamsheer, Barbara Oehl-Jaschkowitz, Lars Wittler, Deepthi de Silva, Ingo Kurth, Idit Maya, Fernando Santos-Simarro, Wiebke Hülsemann, Eva Klopocki, Roger Mountford, Alan Fryer, Guntram Borck, Denise Horn, Pablo Lapunzina, Meredith Wilson, Bénédicte Mascrez, Denis Duboule, Stefan Mundlos, Malte Spielmann
PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis-regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing...
October 12, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://www.readbyqxmd.com/read/29230162/a-novel-de-novo-fzd2-mutation-in-a-patient-with-autosomal-dominant-omodysplasia
#9
Seval Türkmen, Malte Spielmann, Nilay Güneş, Alexej Knaus, Ricarda Flöttmann, Stefan Mundlos, Beyhan Tüysüz
We described a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 ( FZD2 ) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits. The findings of our patient were compared to an autosomal dominant omodysplasia (OMOD2) family with FZD2 mutation reported in the literature. OMOD2 is a rare skeletal dysplasia and characterized by facial dysmorphism and shortness of the upper extremities and first metacarpal bones...
November 2017: Molecular Syndromology
https://www.readbyqxmd.com/read/29222456/bmps-as-new-insulin-sensitizers-enhanced-glucose-uptake-in-mature-3t3-l1-adipocytes-via-ppar%C3%AE-and-glut4-upregulation
#10
Isabelle Schreiber, Gina Dörpholz, Claus-Eric Ott, Bjørt Kragesteen, Nancy Schanze, Cory Thomas Lee, Josef Köhrle, Stefan Mundlos, Karen Ruschke, Petra Knaus
Insulin-resistance is the main cause of type 2 diabetes. Here we describe the identification and characterization of BMP2 and BMP6 as new insulin-sensitizing growth factors in mature adipocytes. We show that BMP2 and BMP6 lead to enhanced insulin-mediated glucose uptake in both insulin-sensitive and -insensitive adipocytes. We exclude a direct effect of BMP2 or BMP6 on translocation of GLUT4 to the plasma membrane and demonstrate that these BMPs increase GLUT4 protein levels equipotent to Rosiglitazone. BMPs induce expression of PPARγ as the crucial mediator for the insulin-sensitizing effect...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29100093/de-novo-mutations-in-slc25a24-cause-a-craniosynostosis-syndrome-with-hypertrichosis-progeroid-appearance-and-mitochondrial-dysfunction
#11
Nadja Ehmke, Luitgard Graul-Neumann, Lukasz Smorag, Rainer Koenig, Lara Segebrecht, Pilar Magoulas, Fernando Scaglia, Esra Kilic, Anna F Hennig, Nicolai Adolphs, Namrata Saha, Beatrix Fauler, Vera M Kalscheuer, Friederike Hennig, Janine Altmüller, Christian Netzer, Holger Thiele, Peter Nürnberg, Gökhan Yigit, Marten Jäger, Jochen Hecht, Ulrike Krüger, Thorsten Mielke, Peter M Krawitz, Denise Horn, Markus Schuelke, Stefan Mundlos, Carlos A Bacino, Penelope E Bonnen, Bernd Wollnik, Björn Fischer-Zirnsak, Uwe Kornak
Gorlin-Chaudhry-Moss syndrome (GCMS) is a dysmorphic syndrome characterized by coronal craniosynostosis and severe midface hypoplasia, body and facial hypertrichosis, microphthalmia, short stature, and short distal phalanges. Variable lipoatrophy and cutis laxa are the basis for a progeroid appearance. Using exome and genome sequencing, we identified the recurrent de novo mutations c.650G>A (p.Arg217His) and c.649C>T (p.Arg217Cys) in SLC25A24 in five unrelated girls diagnosed with GCMS. Two of the girls had pronounced neonatal progeroid features and were initially diagnosed with Wiedemann-Rautenstrauch syndrome...
November 2, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29042476/the-three-dimensional-genome-regulating-gene-expression-during-pluripotency-and-development
#12
REVIEW
Guillaume Andrey, Stefan Mundlos
The precise expression of genes in time and space during embryogenesis is largely influenced by communication between enhancers and promoters, which is propagated and governed by the physical proximity of these elements in the nucleus. Here, we review how chromatin domains organize the genome by guiding enhancers to their target genes thereby preventing non-specific interactions with other neighboring regions. We also discuss the dynamics of chromatin interactions between enhancers and promoters, as well as the consequent changes in gene expression, that occur in pluripotent cells and during development...
October 15, 2017: Development
https://www.readbyqxmd.com/read/28846100/composition-and-dosage-of-a-multipartite-enhancer-cluster-control-developmental-expression-of-ihh-indian-hedgehog
#13
Anja J Will, Giulia Cova, Marco Osterwalder, Wing-Lee Chan, Lars Wittler, Norbert Brieske, Verena Heinrich, Jean-Pierre de Villartay, Martin Vingron, Eva Klopocki, Axel Visel, Darío G Lupiáñez, Stefan Mundlos
Copy number variations (CNVs) often include noncoding sequences and putative enhancers, but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of IHH (encoding Indian hedgehog), which cause multiple, highly localized phenotypes including craniosynostosis and synpolydactyly. We show through transgenic reporter and genome-editing studies in mice that Ihh is regulated by a constellation of at least nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips...
October 2017: Nature Genetics
https://www.readbyqxmd.com/read/28559208/novel-splice-mutation-in-lrp4-causes-severe-type-of-cenani-lenz-syndactyly-syndrome-with-oro-facial-and-skeletal-symptoms
#14
Muhammad Afzal, Qamar Zaman, Uwe Kornak, Stefan Mundlos, Sajid Malik, Ricarda Flöttmann
Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney...
August 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/28103242/genome-wide-binding-of-posterior-hoxa-d-transcription-factors-reveals-subgrouping-and-association-with-ctcf
#15
Ivana Jerković, Daniel M Ibrahim, Guillaume Andrey, Stefan Haas, Peter Hansen, Catrin Janetzki, Irene González Navarrete, Peter N Robinson, Jochen Hecht, Stefan Mundlos
Homeotic genes code for key transcription factors (HOX-TFs) that pattern the animal body plan. During embryonic development, Hox genes are expressed in overlapping patterns and function in a partially redundant manner. In vitro biochemical screens probing the HOX-TF sequence specificity revealed largely overlapping sequence preferences, indicating that co-factors might modulate the biological function of HOX-TFs. However, due to their overlapping expression pattern, high protein homology, and insufficiently specific antibodies, little is known about their genome-wide binding preferences...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/27924012/l1base-2-more-retrotransposition-active-line-1s-more-mammalian-genomes
#16
Tobias Penzkofer, Marten Jäger, Marek Figlerowicz, Richard Badge, Stefan Mundlos, Peter N Robinson, Tomasz Zemojtel
LINE-1 (L1) insertions comprise as much as 17% of the human genome sequence, and similar proportions have been recorded for other mammalian species. Given the established role of L1 retrotransposons in shaping mammalian genomes, it becomes an important task to track and annotate the sources of this activity: full length elements, able to encode the cis and trans acting components of the retrotransposition machinery. The L1Base database (http://l1base.charite.de) contains annotated full-length sequences of LINE-1 transposons including putatively active L1s...
January 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923844/characterization-of-hundreds-of-regulatory-landscapes-in-developing-limbs-reveals-two-regimes-of-chromatin-folding
#17
Guillaume Andrey, Robert Schöpflin, Ivana Jerković, Verena Heinrich, Daniel M Ibrahim, Christina Paliou, Myriam Hochradel, Bernd Timmermann, Stefan Haas, Martin Vingron, Stefan Mundlos
Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location, and dynamics of their associated regulatory elements are unknown. In this work, we characterized the three-dimensional chromatin microarchitecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq, and RNA-seq in forelimb, hindlimb at three developmental stages, and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains...
February 2017: Genome Research
https://www.readbyqxmd.com/read/27706140/formation-of-new-chromatin-domains-determines-pathogenicity-of-genomic-duplications
#18
Martin Franke, Daniel M Ibrahim, Guillaume Andrey, Wibke Schwarzer, Verena Heinrich, Robert Schöpflin, Katerina Kraft, Rieke Kempfer, Ivana Jerković, Wing-Lee Chan, Malte Spielmann, Bernd Timmermann, Lars Wittler, Ingo Kurth, Paola Cambiaso, Orsetta Zuffardi, Gunnar Houge, Lindsay Lambie, Francesco Brancati, Ana Pombo, Martin Vingron, Francois Spitz, Stefan Mundlos
Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology...
October 13, 2016: Nature
https://www.readbyqxmd.com/read/27604556/a-de-novo-1q23-3-q24-2-deletion-combined-with-a-gorab-missense-mutation-causes-a-distinctive-phenotype-with-cutis-laxa
#19
Mohammed Al-Bughaili, Teresa M Neuhann, Ricarda Flöttmann, Stefan Mundlos, Malte Spielmann, Uwe Kornak, Björn Fischer-Zirnsak
Gerodermia osteodysplastica is a recessive segmental progeroid disorder mainly characterized by wrinkled skin, generalized connective tissue weakness, infantile onset osteoporosis and normal intelligence. Coding mutations in GORAB, localized on chromosome 1q24.2, are the cause of this disease. 1q24 deletions underlie a spectrum of disorders with intellectual disability and ear abnormalities as phenotypic hallmarks. Here we report on an individual from Azerbaijan originating from a non-consanguineous couple showing short stature, cutis laxa, frequent fractures, facial dysmorphism, cup-shaped ears and intellectual disability...
February 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/27565584/a-likelihood-ratio-based-method-to-predict-exact-pedigrees-for-complex-families-from-next-generation-sequencing-data
#20
Verena Heinrich, Tom Kamphans, Stefan Mundlos, Peter N Robinson, Peter M Krawitz
MOTIVATION: Next generation sequencing technology considerably changed the way we screen for pathogenic mutations in rare Mendelian disorders. However, the identification of the disease-causing mutation amongst thousands of variants of partly unknown relevance is still challenging and efficient techniques that reduce the genomic search space play a decisive role. Often segregation- or linkage analysis are used to prioritize candidates, however, these approaches require correct information about the degree of relationship among the sequenced samples...
January 1, 2017: Bioinformatics
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