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Stefan mundlos

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
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
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 ( contains annotated full-length sequences of LINE-1 transposons including putatively active L1s...
January 4, 2017: Nucleic Acids Research
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
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
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
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
Wenke Seifert, York Posor, Peter Schu, Gudrun Stenbeck, Stefan Mundlos, Sabine Klaassen, Peter Nürnberg, Volker Haucke, Uwe Kornak, Jirko Kühnisch
Dominant or recessive mutations in the progressive ankylosis gene ANKH have been linked with familial chondrocalcinosis (CCAL2), craniometaphyseal dysplasia (CMD), and mental retardation, deafness, ankylosis syndrome (MRDA). The function of the encoded membrane protein ANK in cellular compartments other than the plasma membrane is unknown. Here, we show that ANK localizes to the trans-Golgi network (TGN), clathrin-coated vesicles, and the plasma membrane. ANK functionally interacts with clathrin and clathrin associated adaptor protein (AP) complexes as loss of either protein causes ANK dispersion from the TGN to cytoplasmic endosome-like puncta...
July 27, 2016: Human Molecular Genetics
Malte Spielmann, Stefan Mundlos
Over the past decades the search for disease causing variants has been focusing exclusively on the coding genome. This highly selective approach has been extremely successful resulting in the identification of thousands of disease genes, but ignores the functional and therefore disease relevance of the rest of the genome. Dropping sequencing costs and new high-throughput technologies such as ChIP-seq and chromosome conformation capture have opened new possibilities for the systematic investigation of the non-coding genome...
October 1, 2016: Human Molecular Genetics
Alexej Knaus, Tomonari Awaya, Ingo Helbig, Zaid Afawi, Manuela Pendziwiat, Jubran Abu-Rachma, Miles D Thompson, David E Cole, Steve Skinner, Fran Annese, Natalie Canham, Michal R Schweiger, Peter N Robinson, Stefan Mundlos, Taroh Kinoshita, Arnold Munnich, Yoshiko Murakami, Denise Horn, Peter M Krawitz
HPMRS or Mabry syndrome is a heterogeneous glycosylphosphatidylinositol (GPI) anchor deficiency that is caused by an impairment of synthesis or maturation of the GPI-anchor. The expressivity of the clinical features in HPMRS varies from severe syndromic forms with multiple organ malformations to mild nonsyndromic intellectual disability. In about half of the patients with the clinical diagnosis of HPMRS, pathogenic mutations can be identified in the coding region in one of the six genes, one among them is PGAP3...
August 2016: Human Mutation
Darío G Lupiáñez, Malte Spielmann, Stefan Mundlos
Spatial organization is an inherent property of the vertebrate genome to accommodate the roughly 2m of DNA in the nucleus of a cell. In this nonrandom organization, topologically associating domains (TADs) emerge as a fundamental structural unit that is thought to guide regulatory elements to their cognate promoters. In this review we summarize the most recent findings about TADs and the boundary regions separating them. We discuss how the disruption of these structures by genomic rearrangements can result in gene misexpression and disease...
April 2016: Trends in Genetics: TIG
Malte Spielmann, Sylvie Marx, Gotthold Barbi, Ricarda Flöttmann, Hildegard Kehrer-Sawatzki, Rainer König, Denise Horn, Stefan Mundlos, Sean Nader, Guntram Borck
The femoral facial syndrome (FFS) is a rare congenital anomaly syndrome characterized by bilateral femoral hypoplasia and facial dysmorphism. The etiology of FFS is currently unknown but maternal/gestational diabetes has been proposed as a strong risk factor for syndromic femoral hypoplasia. In affected children born to non-diabetic mothers, a genetic contribution to FFS is suspected; however, no chromosomal anomalies or gene mutations have been identified so far. Here, we report on a girl with FFS and a de novo complex chromosome rearrangement of terminal chromosome 2q37...
May 2016: American Journal of Medical Genetics. Part A
Luisa Mackenroth, Björn Fischer-Zirnsak, Johannes Egerer, Jochen Hecht, Tilmann Kallinich, Werner Stenzel, Birgit Spors, Arpad von Moers, Stefan Mundlos, Uwe Kornak, Kerstin Gerhold, Denise Horn
Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p...
April 2016: American Journal of Medical Genetics. Part A
Ricarda Flöttmann, Anna Sowinska-Seidler, Julie Lavie, Jean-François Chateil, Didier Lacombe, Stefan Mundlos, Denise Horn, Malte Spielmann
Parathyroid hormone-like hormone (PTHLH, MIM 168470) plays an important role in endochondral bone development and prevents chondrocytes from differentiating. Disease-causing variants and haploinsufficiency of PTHLH are known to cause brachydactyly type E and short stature. So far, three large duplications encompassing several genes including PTHLH associating with enchondromatas and acro-osteolysis have been described in the literature. Here, we report on a three-generation pedigree with short humerus, curved radius, and a specific type of severe brachydactyly with features of types E and A1 but without the enchondromatas and the acro-osteolysis...
August 2016: European Journal of Human Genetics: EJHG
Daniel M Ibrahim, Naeimeh Tayebi, Alexej Knaus, Asita C Stiege, Afsaneh Sahebzamani, Jochen Hecht, Stefan Mundlos, Malte Spielmann
Synpolydactyly (SPD) is a rare congenital limb disorder characterized by syndactyly between the third and fourth fingers and an additional digit in the syndactylous web. In most cases SPD is caused by heterozygous mutations in HOXD13 resulting in the expansion of a N-terminal polyalanine tract. If homozygous, the mutation results in severe shortening of all metacarpals and phalanges with a morphological transformation of metacarpals to carpals. Here, we describe a novel homozygous missense mutation in a family with unaffected consanguineous parents and severe brachydactyly and metacarpal-to-carpal transformation in the affected child...
March 2016: American Journal of Medical Genetics. Part A
Maja Sukalo, Felix Tilsen, Hülya Kayserili, Dietmar Müller, Beyhan Tüysüz, Deborah M Ruddy, Emma Wakeling, Karen Helene Ørstavik, Nuria C Bramswig, Katie M Snape, Richard Trembath, Maryse De Smedt, Nathalie van der Aa, Martin Skalej, Stefan Mundlos, Wim Wuyts, Laura Southgate, Martin Zenker
The original article to which this Erratum refers was published in Human Mutation 36(6):593–598(DOI:10.1002/humu22795).The authors realized that a co-author, Nuria C. Bramswig, was left off of the title page of this article at the time of submission. This erratum serves to correct this error by including Dr. Bramswig and Dr. Bramswig's institution in the title page information.The authors regret the error.
November 2015: Human Mutation
Björn Fischer-Zirnsak, Nathalie Escande-Beillard, Jaya Ganesh, Yu Xuan Tan, Mohammed Al Bughaili, Angela E Lin, Inderneel Sahai, Paulina Bahena, Sara L Reichert, Abigail Loh, Graham D Wright, Jaron Liu, Elisa Rahikkala, Eniko K Pivnick, Asim F Choudhri, Ulrike Krüger, Tomasz Zemojtel, Conny van Ravenswaaij-Arts, Roya Mostafavi, Irene Stolte-Dijkstra, Sofie Symoens, Leila Pajunen, Lihadh Al-Gazali, David Meierhofer, Peter N Robinson, Stefan Mundlos, Camilo E Villarroel, Peter Byers, Amira Masri, Stephen P Robertson, Ulrike Schwarze, Bert Callewaert, Bruno Reversade, Uwe Kornak
Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS...
September 3, 2015: American Journal of Human Genetics
Na Zhu, Verena Heinrich, Thorsten Dickhaus, Jochen Hecht, Peter N Robinson, Stefan Mundlos, Tom Kamphans, Peter M Krawitz
MOTIVATION: When analyzing a case group of patients with ultra-rare disorders the ethnicities are often diverse and the data quality might vary. The population substructure in the case group as well as the heterogeneous data quality can cause substantial inflation of test statistics and result in spurious associations in case-control studies if not properly adjusted for. Existing techniques to correct for confounding effects were especially developed for common variants and are not applicable to rare variants...
November 15, 2015: Bioinformatics
Emely L Bortel, Georg N Duda, Stefan Mundlos, Bettina M Willie, Peter Fratzl, Paul Zaslansky
This data article contains high resolution (1.2 µm effective pixel size) lab-based micro-computed tomography (µCT) reconstructed volume data of the femoral mid-shafts from young C57BL/6 mice. This data formed the basis for the analyses of bone structural development in healthy mice, including closed and open porosity as reported in Bortel et al. [1]. The data reveals changes seen in bone material and porosity distribution observed when mouse bones transform from porous scaffolds into solid structures during normal organogenesis...
September 2015: Data in Brief
Ricarda Flöttmann, Alexej Knaus, Tomasz Zemojtel, Peter N Robinson, Stefan Mundlos, Denise Horn, Malte Spielmann
Pfeiffer syndrome (MIM: #101600) is a rare autosomal dominant disorder classically characterized by limb and craniofacial anomalies. It is caused by heterozygous mutations in the fibroblast growth factor receptors types 1 and 2 (FGFR1 and FGFR2). We applied a next generation sequencing (NGS) panel approach comprising all 2877 genes currently known to be causative for one or more Mendelian diseases combined with the phenotype based computational tool PhenIX (Phenotypic Interpretation of eXomes). We report on a patient presenting with multiple anomalies of hands and feet including brachydactyly and symphalangism...
August 2015: European Journal of Medical Genetics
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