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JOURNAL ARTICLE
Johannes Kopp, Leonard A Koch, Hristiana Lyubenova, Oliver Küchler, Manuel Holtgrewe, Andranik Ivanov, Christele Dubourg, Erika Launay, Sebastian Brachs, Stefan Mundlos, Nadja Ehmke, Dominik Seelow, Mélanie Fradin, Uwe Kornak, Björn Fischer-Zirnsak
Generalized lipodystrophy is a feature of various hereditary disorders, often leading to a progeroid appearance. In the present study we identified a missense and a frameshift variant in a compound heterozygous state in SUPT7L in a boy with intrauterine growth retardation, generalized lipodystrophy, and additional progeroid features. SUPT7L encodes a component of the transcriptional coactivator complex STAGA. By transcriptome sequencing, we showed the predicted missense variant to cause aberrant splicing, leading to exon truncation and thereby to a complete absence of SUPT7L in dermal fibroblasts...
April 9, 2024: Human Genetics
#2
JOURNAL ARTICLE
Lion Raaz, Paul-Lennard Mendez, Stefan Mundlos, Petra Knaus, Jerome Jatzlau
Chromatin accessibility influences gene regulation and can be quantified using assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq). Recapitulating in vivo fluid shear stress (FSS) mechano-regimes in vitro allows the study of atheroprone and atheroprotective mechanisms. In this protocol, we show how to culture and harvest endothelial cells from microfluidic channels for the preparation of ATAC-seq, highlighting optional growth factor stimulation and different FSS rates...
February 7, 2024: STAR protocols
#3
JOURNAL ARTICLE
Dominik Spira, Susanne Herbst, Sarina Schwartzmann, Véronique Dutrannoy, Elisabeth Steinhagen-Thiessen, Ilja Demuth, Lukas Maurer, Knut Mai, Joachim Spranger, Stefan Mundlos, Thomas Bobbert
OBJECTIVE: Determining the cause of severe insulin resistance and early-onset diabetes in the case of a young woman in which a wide range of differential diagnoses did not apply. RESEARCH DESIGN AND METHODS: Diagnostic workup including medical history, physical examination, specialist consultations, imaging methods, laboratory assessment, and genetic testing carried out by next-generation panel sequencing. RESULTS: After ruling out several differential diagnoses, genetic testing revealed a previously unknown homozygous variant within the canonical splice site of intron 4 in the WRN gene classified as pathogenic...
January 26, 2024: Diabetes Care
#4
JOURNAL ARTICLE
Janna Mitscherling, Henrike L Sczakiel, Olga Kiskemper-Nestorjuk, Sibylle Winterhalter, Stefan Mundlos, Theodosia Bartzela, Martin A Mensah
BACKGROUND/OBJECTIVES: Tooth agenesis (TA) is among the most common malformations in humans. Although several causative mutations have been described, the genetic cause often remains elusive. Here, we test whether whole genome sequencing (WGS) could bridge this diagnostic gap. METHODS: In four families with TA, we assessed the dental phenotype using the Tooth Agenesis Code after intraoral examination and radiographic and photographic documentation. We performed WGS of index patients and subsequent segregation analysis...
December 9, 2023: Oral Diseases
#5
Uirá Souto Melo, Jerome Jatzlau, Cesar A Prada-Medina, Elisabetta Flex, Sunhild Hartmann, Salaheddine Ali, Robert Schöpflin, Laura Bernardini, Andrea Ciolfi, M-Hossein Moeinzadeh, Marius-Konstantin Klever, Aybuge Altay, Pedro Vallecillo-García, Giovanna Carpentieri, Massimo Delledonne, Melanie-Jasmin Ort, Marko Schwestka, Giovanni Battista Ferrero, Marco Tartaglia, Alfredo Brusco, Manfred Gossen, Dirk Strunk, Sven Geißler, Stefan Mundlos, Sigmar Stricker, Petra Knaus, Elisa Giorgio, Malte Spielmann
No abstract text is available yet for this article.
October 9, 2023: Nature Communications
#6
JOURNAL ARTICLE
Jerome Jatzlau, Paul-Lennard Mendez, Aybuge Altay, Lion Raaz, Yufei Zhang, Sophia Mähr, Akin Sesver, Maria Reichenbach, Stefan Mundlos, Martin Vingron, Petra Knaus
Bone morphogenetic protein (BMP) signaling and fluid shear stress (FSS) mediate complementary functions in vascular homeostasis and disease development. It remains to be shown whether altered chromatin accessibility downstream of BMP and FSS offers a crosstalk level to explain changes in SMAD-dependent transcription. Here, we employed ATAC-seq to analyze arterial endothelial cells stimulated with BMP9 and/or FSS. We found that BMP9-sensitive regions harbor non-palindromic GC-rich SMAD-binding elements (GGCTCC) and 69...
September 15, 2023: IScience
#7
JOURNAL ARTICLE
Marius-Konstantin Klever, Eric Sträng, Sara Hetzel, Julius Jungnitsch, Anna Dolnik, Robert Schöpflin, Jens-Florian F Schrezenmeier, Felix Schick, Olga Blau, Jörg Westermann, Frank G Rücker, Zuyao Xia, Konstanze Döhner, Hubert Schrezenmeier, Malte Spielmann, Alexander Meissner, Uira Souto Melo, Stefan Mundlos, Lars Bullinger
Acute myeloid leukemia with complex karyotype (CK-AML) is associated with poor prognosis, which is only in part explained by underlying TP53 mutations. Especially in the presence of complex chromosomal rearrangements, such as chromothripsis, the outcome of CK-AML is dismal. However, this degree of complexity of genomic rearrangements contributes to the leukemogenic phenotype and treatment resistance of CK-AML remains largely unknown. Applying an integrative workflow for the detection of structural variants (SVs) based on Oxford Nanopore (ONT) genomic DNA long-read sequencing (gDNA-LRS) and high-throughput chromosome confirmation capture (Hi-C) in a well-defined cohort of CK-AML identified regions with an extreme density of SVs...
August 15, 2023: Blood Advances
#8
JOURNAL ARTICLE
Maria E Stefanova, Elizabeth Ing-Simmons, Stefan Stefanov, Ilya Flyamer, Heathcliff Dorado Garcia, Robert Schöpflin, Anton G Henssen, Juan M Vaquerizas, Stefan Mundlos
In this study, we delve into the impact of genotoxic anticancer drug treatment on the chromatin structure of human cells, with a particular focus on the effects of doxorubicin. Using Hi-C, ChIP-seq, and RNA-seq, we explore the changes in chromatin architecture brought about by doxorubicin and ICRF193. Our results indicate that physiologically relevant doses of doxorubicin lead to a local reduction in Hi-C interactions in certain genomic regions that contain active promoters, with changes in chromatin architecture occurring independently of Top2 inhibition, cell cycle arrest, and differential gene expression...
August 4, 2023: Cells
#9
JOURNAL ARTICLE
Annika Gottschalk, Henrike L Sczakiel, Wiebke Hülsemann, Sarina Schwartzmann, Angela T Abad-Perez, Johannes Grünhagen, Claus-Eric Ott, Malte Spielmann, Denise Horn, Stefan Mundlos, Aleksander Jamsheer, Martin A Mensah
PURPOSE: HOXD13 is an important regulator of limb development. Pathogenic variants in HOXD13 cause synpolydactyly type 1 (SPD1). How different types and positions of HOXD13 variants contribute to genotype-phenotype correlations, penetrance and expressivity of SPD1 remains elusive. Here, we present a novel cohort and a literature review to elucidate HOXD13 phenotype-genotype correlations. METHODS: Patients with limb anomalies suggestive of SPD1 were selected for analysis of HOXD13 by Sanger sequencing, repeat length analysis and NGS...
July 6, 2023: Genetics in Medicine: Official Journal of the American College of Medical Genetics
#10
REVIEW
Lila Allou, Stefan Mundlos
Deletions, duplications, insertions, inversions, and translocations, collectively called structural variations (SVs), affect more base pairs of the genome than any other sequence variant. The recent technological advancements in genome sequencing have enabled the discovery of tens of thousands of SVs per human genome. These SVs primarily affect non-coding DNA sequences, but the difficulties in interpreting their impact limit our understanding of human disease etiology. The functional annotation of non-coding DNA sequences and methodologies to characterize their three-dimensional (3D) organization in the nucleus have greatly expanded our understanding of the basic mechanisms underlying gene regulation, thereby improving the interpretation of SVs for their pathogenic impact...
June 29, 2023: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
#11
Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, Stefan Mundlos
No abstract text is available yet for this article.
May 18, 2023: Nature Communications
#12
JOURNAL ARTICLE
Rocío Chamorro González, Thomas Conrad, Maja C Stöber, Robin Xu, Mădălina Giurgiu, Elias Rodriguez-Fos, Katharina Kasack, Lotte Brückner, Eric van Leen, Konstantin Helmsauer, Heathcliff Dorado Garcia, Maria E Stefanova, King L Hung, Yi Bei, Karin Schmelz, Marco Lodrini, Stefan Mundlos, Howard Y Chang, Hedwig E Deubzer, Sascha Sauer, Angelika Eggert, Johannes H Schulte, Roland F Schwarz, Kerstin Haase, Richard P Koche, Anton G Henssen
Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact...
May 4, 2023: Nature Genetics
#13
JOURNAL ARTICLE
Konstantin Okonechnikov, Aylin Camgöz, Owen Chapman, Sameena Wani, Donglim Esther Park, Jens-Martin Hübner, Abhijit Chakraborty, Meghana Pagadala, Rosalind Bump, Sahaana Chandran, Katerina Kraft, Rocio Acuna-Hidalgo, Derek Reid, Kristin Sikkink, Monika Mauermann, Edwin F Juarez, Anne Jenseit, James T Robinson, Kristian W Pajtler, Till Milde, Natalie Jäger, Petra Fiesel, Ling Morgan, Sunita Sridhar, Nicole G Coufal, Michael Levy, Denise Malicki, Charlotte Hobbs, Stephen Kingsmore, Shareef Nahas, Matija Snuderl, John Crawford, Robert J Wechsler-Reya, Tom Belle Davidson, Jennifer Cotter, George Michaiel, Gudrun Fleischhack, Stefan Mundlos, Anthony Schmitt, Hannah Carter, Kulandaimanuvel Antony Michealraj, Sachin A Kumar, Michael D Taylor, Jeremy Rich, Frank Buchholz, Jill P Mesirov, Stefan M Pfister, Ferhat Ay, Jesse R Dixon, Marcel Kool, Lukas Chavez
Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression...
April 21, 2023: Nature Communications
#14
JOURNAL ARTICLE
Uirá Souto Melo, Jerome Jatzlau, Cesar A Prada-Medina, Elisabetta Flex, Sunhild Hartmann, Salaheddine Ali, Robert Schöpflin, Laura Bernardini, Andrea Ciolfi, M-Hossein Moeinzadeh, Marius-Konstantin Klever, Aybuge Altay, Pedro Vallecillo-García, Giovanna Carpentieri, Massimo Delledonne, Melanie-Jasmin Ort, Marko Schwestka, Giovanni Battista Ferrero, Marco Tartaglia, Alfredo Brusco, Manfred Gossen, Dirk Strunk, Sven Geißler, Stefan Mundlos, Sigmar Stricker, Petra Knaus, Elisa Giorgio, Malte Spielmann
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification...
April 11, 2023: Nature Communications
#15
JOURNAL ARTICLE
Giulia Cova, Juliane Glaser, Robert Schöpflin, Cesar Augusto Prada-Medina, Salaheddine Ali, Martin Franke, Rita Falcone, Miriam Federer, Emanuela Ponzi, Romina Ficarella, Francesca Novara, Lars Wittler, Bernd Timmermann, Mattia Gentile, Orsetta Zuffardi, Malte Spielmann, Stefan Mundlos
Split-Hand/Foot Malformation type 3 (SHFM3) is a congenital limb malformation associated with tandem duplications at the LBX1/FGF8 locus. Yet, the disease patho-mechanism remains unsolved. Here we investigate the functional consequences of SHFM3-associated rearrangements on chromatin conformation and gene expression in vivo in transgenic mice. We show that the Lbx1/Fgf8 locus consists of two separate, but interacting, regulatory domains. Re-engineering of a SHFM3-associated duplication and a newly reported inversion in mice results in restructuring of the chromatin architecture...
March 17, 2023: Nature Communications
#16
JOURNAL ARTICLE
Sheila Unger, Carlos R Ferreira, Geert R Mortier, Houda Ali, Débora R Bertola, Alistair Calder, Daniel H Cohn, Valerie Cormier-Daire, Katta M Girisha, Christine Hall, Deborah Krakow, Outi Makitie, Stefan Mundlos, Gen Nishimura, Stephen P Robertson, Ravi Savarirayan, David Sillence, Marleen Simon, V Reid Sutton, Matthew L Warman, Andrea Superti-Furga
The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms...
February 13, 2023: American Journal of Medical Genetics. Part A
#17
JOURNAL ARTICLE
Martin A Mensah, Henri Niskanen, Alexandre P Magalhaes, Shaon Basu, Martin Kircher, Henrike L Sczakiel, Alisa M V Reiter, Jonas Elsner, Peter Meinecke, Saskia Biskup, Brian H Y Chung, Gregor Dombrowsky, Christel Eckmann-Scholz, Marc Phillip Hitz, Alexander Hoischen, Paul-Martin Holterhus, Wiebke Hülsemann, Kimia Kahrizi, Vera M Kalscheuer, Anita Kan, Mandy Krumbiegel, Ingo Kurth, Jonas Leubner, Ann Carolin Longardt, Jörg D Moritz, Hossein Najmabadi, Karolina Skipalova, Lot Snijders Blok, Andreas Tzschach, Eberhard Wiedersberg, Martin Zenker, Carla Garcia-Cabau, René Buschow, Xavier Salvatella, Matthew L Kraushar, Stefan Mundlos, Almuth Caliebe, Malte Spielmann, Denise Horn, Denes Hnisz
Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3 . Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5 . This suggests that mutations in disordered proteins may alter condensate properties and function6-8 . Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function...
February 8, 2023: Nature
#18
JOURNAL ARTICLE
Alejandro Castilla-Ibeas, Sofía Zdral, Laura Galán, Endika Haro, Lila Allou, Víctor M Campa, Jose M Icardo, Stefan Mundlos, Kerby C Oberg, Marian A Ros
Mammalian digit tip regeneration is linked to the presence of nail tissue, but a nail-explicit model is missing. Here, we report that nail-less double-ventral digits of ΔLARM1/2 mutants that lack limb-specific Lmx1b enhancers fail to regenerate. To separate the nail's effect from the lack of dorsoventral (DV) polarity, we also interrogate double-dorsal double-nail digits and show that they regenerate. Thus, DV polarity is not a prerequisite for regeneration, and the nail requirement is supported. Transcriptomic comparison between wild-type and non-regenerative ΔLARM1/2 mutant blastemas reveals differential upregulation of vascularization and connective tissue functional signatures in wild type versus upregulation of inflammation in the mutant...
January 13, 2023: Cell Reports
#19
JOURNAL ARTICLE
Robert Schöpflin, Uirá Souto Melo, Hossein Moeinzadeh, David Heller, Verena Laupert, Jakob Hertzberg, Manuel Holtgrewe, Nico Alavi, Marius-Konstantin Klever, Julius Jungnitsch, Emel Comak, Seval Türkmen, Denise Horn, Yannis Duffourd, Laurence Faivre, Patrick Callier, Damien Sanlaville, Orsetta Zuffardi, Romano Tenconi, Nehir Edibe Kurtas, Sabrina Giglio, Bettina Prager, Anna Latos-Bielenska, Ida Vogel, Merete Bugge, Niels Tommerup, Malte Spielmann, Antonio Vitobello, Vera M Kalscheuer, Martin Vingron, Stefan Mundlos
Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions...
October 29, 2022: Nature Communications
#20
JOURNAL ARTICLE
Luis Francisco González Álvarez, Jair Tenorio-Castaño, Fernando A Poletta, Fernando Santos-Simarro, Pedro Arias, Natalia Gallego, Iêda Maria Orioli, Stefan Mundlos, Eduardo E Castilla, Víctor Martínez-Glez, María Luisa Martínez-Frías, Víctor L Ruiz-Pérez, Julián Nevado, Pablo Lapunzina
We present a large, ten-generation family of 273 individuals with 84 people having preaxial polydactyly/triphalangeal thumb due to a pathogenic variant in the zone of polarizing activity regulatory sequence (ZRS) within the exon 5 of LMBR1. The causative change maps to position 396 of the ZRS, located at position c.423 + 4909C > T (chr7:156791480; hg38; LMBR1 ENST00000353442.10; rs606231153 NG_009240.2) in the intron 5 of LMBR1. The first affected individual with the disorder was traced back to mid-1700, when some settlers and workers established in Cervera de Buitrago, a small village about 82 km North to Madrid...
October 29, 2022: American Journal of Medical Genetics. Part A
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