@article{GraserLiedtkeJakob2021, author = {Graser, Stephanie and Liedtke, Daniel and Jakob, Franz}, title = {TNAP as a new player in chronic inflammatory conditions and metabolism}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms22020919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258888}, year = {2021}, abstract = {This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here.}, language = {en} } @phdthesis{Klein2001, author = {Klein, Andreas}, title = {Der altersabh{\"a}ngige Verlust der Geschlechtschromosomen beim Menschen unter Einwirkung von 5-Azadeoxycytidin}, doi = {10.25972/OPUS-32771}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-327714}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2001}, abstract = {Die vorliegende Arbeit untersucht, ob mit zunehmendem Alter w{\"a}hrend der Mitose h{\"a}ufiger Geschlechtschromsomen verlorengehen. Die Beobachtungen erfolgten an Lymphozytenkulturen gesunder weiblicher und m{\"a}nnlicher Probanden aus drei verschiedenen Altersgruppen. Unter Zugabe von 5-Azadeoxycytidin, einem Nukleosidanalogon, ergab sich in den h{\"o}heren Altersgruppen ein verst{\"a}rktes Auftreten von Mikronuklei. Mikronuklei enthalten Chromosomen oder -bruchst{\"u}cke, die w{\"a}hrend der Mitose nicht in die Tochterzellkerne integriert wurden. Mittels in situ Hybridisierung konnte in den Mikronuklei der Frauen zu 5,5 Prozent ein X-Chromosom, bei den M{\"a}nnern mit 10,7 Prozent {\"u}berzuf{\"a}llig h{\"a}ufig ein Y-Chromosom nachgewiesen werden. Zwischen den einzelnen Altersstufen {\"a}nderte sich dieser Anteil nicht wesentlich. 5-Azadeoxycytidin wird als Nukleosidanalogon w{\"a}hrend der Replikation in die DNA eingebaut und verhindert die Methylierung des Tochterstrangs, da ein Kohlenstoffatom im Pyrimidinrings durch ein Stickstoffatom substituiert ist. Wahrscheinlich resultiert aus der Hyomethylierung eine falsche "Verpackung" des Gonosoms w{\"a}hrend der Mitose, dadurch erfolgt eine fehlerhafte Aufteilung des Chromosoms mit Bildung eines Mikronukleus.}, language = {de} } @article{LorenzKressZaumetal.2021, author = {Lorenz, Delia and Kress, Wolfram and Zaum, Ann-Kathrin and Speer, Christian P. and Hebestreit, Helge}, title = {Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency}, series = {BMC Pediatrics}, volume = {21}, journal = {BMC Pediatrics}, doi = {10.1186/s12887-021-02767-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261084}, year = {2021}, abstract = {Background The spondylodysplastic Ehlers-Danlos subtype (OMIM \#130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. Presentation of cases We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. Conclusions This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.}, language = {en} } @article{VonaMaroofianBellacchioetal.2018, author = {Vona, Barbara and Maroofian, Reza and Bellacchio, Emanuele and Najafi, Maryam and Thompson, Kyle and Alahmad, Ahmad and He, Langping and Ahangari, Najmeh and Rad, Abolfazl and Shahrokhzadeh, Sima and Bahena, Paulina and Mittag, Falk and Traub, Frank and Movaffagh, Jebrail and Amiri, Nafise and Doosti, Mohammad and Boostani, Reza and Shirzadeh, Ebrahim and Haaf, Thomas and Diodato, Daria and Schmidts, Miriam and Taylor, Robert W. and Karimiani, Ehsan Ghayoor}, title = {Expanding the clinical phenotype of IARS2-related mitochondrial disease}, series = {BMC Medical Genetics}, volume = {19}, journal = {BMC Medical Genetics}, number = {196}, doi = {10.1186/s12881-018-0709-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176620}, year = {2018}, abstract = {Background: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. Methods: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. Results: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. Conclusions: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.}, language = {en} } @article{OhlebuschBorstFrankenbachetal.2020, author = {Ohlebusch, Barbara and Borst, Angela and Frankenbach, Tina and Klopocki, Eva and Jakob, Franz and Liedtke, Daniel and Graser, Stephanie}, title = {Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, doi = {10.1038/s41598-020-70152-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230024}, year = {2020}, abstract = {Hypophosphatasia (HPP) is a rare genetic disease with diverse symptoms and a heterogeneous severity of onset with underlying mutations in the ALPL gene encoding the ectoenzyme Tissue-nonspecific alkaline phosphatase (TNAP). Considering the establishment of zebrafish (Danio rerio) as a new model organism for HPP, the aim of the study was the spatial and temporal analysis of alpl expression in embryos and adult brains. Additionally, we determined functional consequences of Tnap inhibition on neural and skeletal development in zebrafish. We show that expression of alpl is present during embryonic stages and in adult neuronal tissues. Analyses of enzyme function reveal zones of pronounced Tnap-activity within the telencephalon and the mesencephalon. Treatment of zebrafish embryos with chemical Tnap inhibitors followed by axonal and cartilage/mineralized tissue staining imply functional consequences of Tnap deficiency on neuronal and skeletal development. Based on the results from neuronal and skeletal tissue analyses, which demonstrate an evolutionary conserved role of this enzyme, we consider zebrafish as a promising species for modeling HPP in order to discover new potential therapy strategies in the long-term.}, language = {en} } @article{MairBiskupKressetal.2020, author = {Mair, Dorothea and Biskup, Saskia and Kress, Wolfram and Abicht, Angela and Br{\"u}ck, Wolfgang and Zechel, Sabrina and Knop, Karl Christian and Koenig, Fatima Barbara and Tey, Shelisa and Nikolin, Stefan and Eggermann, Katja and Kurth, Ingo and Ferbert, Andreas and Weis, Joachim}, title = {Differential diagnosis of vacuolar myopathies in the NGS era}, series = {Brain Pathology}, volume = {30}, journal = {Brain Pathology}, number = {5}, doi = {10.1111/bpa.12864}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216048}, pages = {877 -- 896}, year = {2020}, abstract = {Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non-inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late-onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr-caveolinopathy and of limb-girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.}, language = {en} } @article{ZinkSeewaldRohrbachetal.2022, author = {Zink, Miriam and Seewald, Anne and Rohrbach, Mareike and Brodehl, Andreas and Liedtke, Daniel and Williams, Tatjana and Childs, Sarah J. and Gerull, Brenda}, title = {Altered expression of TMEM43 causes abnormal cardiac structure and function in zebrafish}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms23179530}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286025}, year = {2022}, abstract = {Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy.}, language = {en} } @phdthesis{Klein2001, author = {Klein, Andreas}, title = {Der altersabh{\"a}ngige Verlust der Geschlechtschromosomen beim Menschen unter Einwirkung von 5-Azadeoxycytidin}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1181416}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2001}, abstract = {Die vorliegende Arbeit untersucht, ob mit zunehmendem Alter w{\"a}hrend der Mitose h{\"a}ufiger Geschlechtschromsomen verlorengehen. Die Beobachtungen erfolgten an Lymphozytenkulturen gesunder weiblicher und m{\"a}nnlicher Probanden aus drei verschiedenen Altersgruppen. Unter Zugabe von 5-Azadeoxycytidin, einem Nukleosidanalogon, ergab sich in den h{\"o}heren Altersgruppen ein verst{\"a}rktes Auftreten von Mikronuklei. Mikronuklei enthalten Chromosomen oder -bruchst{\"u}cke, die w{\"a}hrend der Mitose nicht in die Tochterzellkerne integriert wurden. Mittels in situ Hybridisierung konnte in den Mikronuklei der Frauen zu 5,5 Prozent ein X-Chromosom, bei den M{\"a}nnern mit 10,7 Prozent {\"u}berzuf{\"a}llig h{\"a}ufig ein Y-Chromosom nachgewiesen werden. Zwischen den einzelnen Altersstufen {\"a}nderte sich dieser Anteil nicht wesentlich. 5-Azadeoxycytidin wird als Nukleosidanalogon w{\"a}hrend der Replikation in die DNA eingebaut und verhindert die Methylierung des Tochterstrangs, da ein Kohlenstoffatom im Pyrimidinrings durch ein Stickstoffatom substituiert ist. Wahrscheinlich resultiert aus der Hyomethylierung eine falsche "Verpackung" des Gonosoms w{\"a}hrend der Mitose, dadurch erfolgt eine fehlerhafte Aufteilung des Chromosoms mit Bildung eines Mikronukleus.}, language = {de} } @book{Baierlein2005, author = {Baierlein, Jochen}, title = {Gesundheitsstatus und Gesundheitssystem in Deutschland und Ungarn : Ungarn auf dem Weg in die Europ{\"a}ische Union}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-15985}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Es wurden Gesundheitsystem und der Gesundheitsstatus von Ungarn und Deutschland dargestellt. Eine kurze Abhandlung der EU-Osterweiterung sowie abschliessend eine Gegen{\"u}berstellung der System.}, language = {de} } @phdthesis{Riemens2023, author = {Riemens, Renzo J. M.}, title = {Neuroepigenomics in Alzheimer's disease: The single cell ADds}, isbn = {978-94-6423-524-1}, doi = {10.25972/OPUS-25457}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254574}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die Forschung, die in dieser Arbeit zusammengestellt wird, kann in zwei Teile geteilt werden. Der erste Teil, bestehend aus vier Kapiteln, konzentriert sich auf die Rolle der epigenetischen Dysregulation in der {\"A}tiopathophysiologie der sporadischen Alzheimer-Krankheit (sAD). Neben Einblicken in die neuesten Entwicklungen in neuroepigenomischen Studien zu dieser Krankheit geht der erste Teil der Arbeit auch auf verbleibende Herausforderungen ein und gibt einen Ausblick auf m{\"o}gliche Entwicklungen auf diesem Gebiet. Der zweite Teil, der drei weitere Kapitel umfasst, konzentriert sich auf die Anwendung von auf induzierten pluripotenten Stammzellen (iPSC) basierenden Krankheitsmodellen f{\"u}r das Studium der AD, einschließlich, aber nicht beschr{\"a}nkt auf mechanistische Studien zur epigenetischen Dysregulation unter Verwendung dieser Plattform. Neben der Skizzierung der bisherigen Forschung mit iPSC-basierten Modellen f{\"u}r sAD gibt der zweite Teil der Arbeit auch Einblicke in die Gewinnung krankheitsrelevanter Nervenkulturen auf Basis der gezielten Differenzierung von iPSCs und beinhaltet dar{\"u}ber hinaus einen experimentellen Ansatz f{\"u}r den Aufbau eines solchen Modellsystems.}, subject = {Epigenetik}, language = {en} } @phdthesis{Doll2024, author = {Doll, Julia}, title = {Identifizierung und Charakterisierung neuer, mit H{\"o}rst{\"o}rungen assoziierter Gene und Varianten mittels Exom-Sequenzierung}, doi = {10.25972/OPUS-26109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261097}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Laut des aktuellen Reports der Weltgesundheitsorganisation sind ca. 466 Millionen Menschen weltweit von einer H{\"o}rst{\"o}rung (HS) betroffen. Durch die enorme Heterogenit{\"a}t und die klinische Variabilit{\"a}t, die diese Erkrankung ausmacht, und viele bisher nicht mit HS assoziierte Gene, bleibt ein großer Teil der erblich bedingten HS in vielen Familien unaufgekl{\"a}rt. Die Entwicklung moderner Techniken, wie die Next-Generation Sequenzierung (NGS) und der Fortschritt bei der Untersuchung von Modellorganismen trugen jedoch in den letzten Jahren immens dazu bei, neue Gene zu identifizieren, die innerhalb des auditorischen Signalwegs oder damit assoziierten Strukturen beteiligt sind. Die vorliegende Arbeit umfasst Ergebnisse dreier Ver{\"o}ffentlichungen, in denen iranische und pakistanische Familien und eine deutsche Familie mit erblich bedingter HS untersucht und neue, krankheitsverursachende Varianten identifiziert und funktionell charakterisiert wurden. Im ersten Abschnitt konnten zwei neue rezessive Varianten im CDC14A-Gen als krankheitsverursachend identifiziert werden, die zu einem potentiellen Funktionsverlust des kodierten Proteins in einer iranischen und einer pakistanischen Familie f{\"u}hren. Mit Hilfe einer funktionellen Charakterisierung auf RNA-Ebene (Spleiß-Assay und RT-qPCR) konnte der Funktionsverlust beider Varianten best{\"a}tigt werden. Der zweite Abschnitt umfasst eine deutsche Familie mit sieben von einer HS betroffenen Familienmitgliedern, in der eine heterozygote missense Variante in MYO3A identifiziert wurde. In der vorliegenden Arbeit konnte somit die erste autosomal dominante Variante in einer europ{\"a}ischen Familie mit einer bilingualen, sensorineuralen Hochtonschwerh{\"o}rigkeit beschrieben werden und der dominante Charakter von MYO3A best{\"a}tigt werden. Im dritten Abschnitt konnten die krankheitsverursachenden Varianten in 13 Familien aus einer Kohorte mit 21 pakistanischen Familien mit einer syndromalen und nicht-syndromalen HS ausfindig gemacht werden. Hierbei wurden sowohl bekannte, als auch bisher nicht beschriebene Varianten detektiert. Die Aufkl{\"a}rungsrate innerhalb dieser Kohorte betrug 61,9\% und es konnte somit das Spektrum syndromaler und nicht-syndromaler HS erweitert werden. Der letzte Abschnitt dieser Arbeit beschreibt eine iranische Familie mit einer milden HS und milden Intelligenzminderung, in der eine homozygote missense Variante im Kandidatengen DBN1 ausfindig gemacht wurde. Um die Funktion und die Auswirkungen eines potentiellen Verlusts des codierten Proteins Drebrin zu untersuchen, wurden immunhistochemische F{\"a}rbungen und auditorische Messungen an Dbn1 Knockout (KO)-M{\"a}usen durchgef{\"u}hrt. Hierbei konnte eine Expression innerhalb der Nervenfasern, die innere Haarzellen innervieren, nachgewiesen werden. Eine leicht verl{\"a}ngerte Latenz f{\"u}r die ABR-Welle IV in KO-M{\"a}usen im Vergleich zum Wildtyp ergab den Hinweis auf einen Defekt innerhalb des zentralen auditorischen Signalwegs, der m{\"o}glicherweise mit einer Sprachverarbeitungsst{\"o}rung im Menschen korreliert.}, subject = {H{\"o}rst{\"o}rung}, language = {de} } @article{LutherBrandtVylkovaetal.2023, author = {Luther, Christian H. and Brandt, Philipp and Vylkova, Slavena and Dandekar, Thomas and M{\"u}ller, Tobias and Dittrich, Marcus}, title = {Integrated analysis of SR-like protein kinases Sky1 and Sky2 links signaling networks with transcriptional regulation in Candida albicans}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {13}, journal = {Frontiers in Cellular and Infection Microbiology}, issn = {2235-2988}, doi = {10.3389/fcimb.2023.1108235}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311771}, year = {2023}, abstract = {Fungal infections are a major global health burden where Candida albicans is among the most common fungal pathogen in humans and is a common cause of invasive candidiasis. Fungal phenotypes, such as those related to morphology, proliferation and virulence are mainly driven by gene expression, which is primarily regulated by kinase signaling cascades. Serine-arginine (SR) protein kinases are highly conserved among eukaryotes and are involved in major transcriptional processes in human and S. cerevisiae. Candida albicans harbors two SR protein kinases, while Sky2 is important for metabolic adaptation, Sky1 has similar functions as in S. cerevisiae. To investigate the role of these SR kinases for the regulation of transcriptional responses in C. albicans, we performed RNA sequencing of sky1Δ and sky2Δ and integrated a comprehensive phosphoproteome dataset of these mutants. Using a Systems Biology approach, we study transcriptional regulation in the context of kinase signaling networks. Transcriptomic enrichment analysis indicates that pathways involved in the regulation of gene expression are downregulated and mitochondrial processes are upregulated in sky1Δ. In sky2Δ, primarily metabolic processes are affected, especially for arginine, and we observed that arginine-induced hyphae formation is impaired in sky2Δ. In addition, our analysis identifies several transcription factors as potential drivers of the transcriptional response. Among these, a core set is shared between both kinase knockouts, but it appears to regulate different subsets of target genes. To elucidate these diverse regulatory patterns, we created network modules by integrating the data of site-specific protein phosphorylation and gene expression with kinase-substrate predictions and protein-protein interactions. These integrated signaling modules reveal shared parts but also highlight specific patterns characteristic for each kinase. Interestingly, the modules contain many proteins involved in fungal morphogenesis and stress response. Accordingly, experimental phenotyping shows a higher resistance to Hygromycin B for sky1Δ. Thus, our study demonstrates that a combination of computational approaches with integration of experimental data can offer a new systems biological perspective on the complex network of signaling and transcription. With that, the investigation of the interface between signaling and transcriptional regulation in C. albicans provides a deeper insight into how cellular mechanisms can shape the phenotype.}, language = {en} } @article{VonaNandaShehataDieleretal.2017, author = {Vona, Barbara and Nanda, Indrajit and Shehata-Dieler, Wafaa and Haaf, Thomas}, title = {Genetics of Tinnitus: Still in its Infancy}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, number = {236}, doi = {10.3389/fnins.2017.00236}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170926}, year = {2017}, abstract = {Tinnitus is the perception of a phantom sound that affects between 10 and 15\% of the general population. Despite this considerable prevalence, treatments for tinnitus are presently lacking. Tinnitus exhibits a diverse array of recognized risk factors and extreme clinical heterogeneity. Furthermore, it can involve an unknown number of auditory and non-auditory networks and molecular pathways. This complex combination has hampered advancements in the field. The identification of specific genetic factors has been at the forefront of several research investigations in the past decade. Nine studies have examined genes in a case-control association approach. Recently, a genome-wide association study has highlighted several potentially significant pathways that are implicated in tinnitus. Two twin studies have calculated a moderate heritability for tinnitus and disclosed a greater concordance rate in monozygotic twins compared to dizygotic twins. Despite the more recent data alluding to genetic factors in tinnitus, a strong association with any specific genetic locus is lacking and a genetic study with sufficient statistical power has yet to be designed. Future research endeavors must overcome the many inherent limitations in previous study designs. This review summarizes the previously embarked upon tinnitus genetic investigations and summarizes the hurdles that have been encountered. The identification of candidate genes responsible for tinnitus may afford gene based diagnostic approaches, effective therapy development, and personalized therapeutic intervention.}, language = {en} } @article{VitaleZoellerJanschetal.2021, author = {Vitale, Maria Rosaria and Z{\"o}ller, Johanna Eva Maria and Jansch, Charline and Janz, Anna and Edenhofer, Frank and Klopocki, Eva and van den Hove, Daniel and Vanmierlo, Tim and Rivero, Olga and Kasri, Nael Nadif and Ziegler, Georg Christoph and Lesch, Klaus-Peter}, title = {Generation of induced pluripotent stem cell (iPSC) lines carrying a heterozygous (UKWMPi002-A-1) and null mutant knockout (UKWMPi002-A-2) of Cadherin 13 associated with neurodevelopmental disorders using CRISPR/Cas9}, series = {Stem Cell Research}, volume = {51}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2021.102169}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260331}, year = {2021}, abstract = {Fibroblasts isolated from a skin biopsy of a healthy 46-year-old female were infected with Sendai virus containing the Yamanaka factors to produce transgene-free human induced pluripotent stem cells (iPSCs). CRISPR/Cas9 was used to generate isogenic cell lines with a gene dose-dependent deficiency of CDH13, a risk gene associated with neurodevelopmental and psychiatric disorders. Thereby, a heterozygous CDH13 knockout (CDH13\(^{+/-}\)) and a CDH13 null mutant (CDH13\(^{-/-}\)) iPSC line was obtained. All three lines showed expression of pluripotency-associated markers, the ability to differentiate into cells of the three germ layers in vitro, and a normal female karyotype.}, language = {en} } @article{KoelbelRoosvanderVenetal.2020, author = {K{\"o}lbel, Heike and Roos, Andreas and van der Ven, Peter F. M. and Evangelista, Teresinha and Nolte, Kay and Johnson, Katherine and T{\"o}pf, Ana and Wilson, Michael and Kress, Wolfram and Sickmann, Albert and Straub, Volker and Kollipara, Laxmikanth and Weis, Joachim and F{\"u}rst, Dieter O. and Schara, Ulrike}, title = {First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC}, series = {Human Mutation}, volume = {41}, journal = {Human Mutation}, number = {9}, doi = {10.1002/humu.24062}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215481}, pages = {1600 -- 1614}, year = {2020}, abstract = {Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal-dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild-type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild-type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.}, language = {en} } @article{WeissbachHerediaGuerreroBarnsteineretal.2020, author = {Weißbach, Susann and Heredia-Guerrero, Sofia Catalina and Barnsteiner, Stefanie and Großhans, Lukas and Bodem, Jochen and Starz, Hanna and Langer, Christian and Appenzeller, Silke and Knop, Stefan and Steinbrunn, Torsten and Rost, Simone and Einsele, Hermann and Bargou, Ralf Christian and Rosenwald, Andreas and St{\"u}hmer, Thorsten and Leich, Ellen}, title = {Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers12020455}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200617}, year = {2020}, abstract = {Approximately 20\% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.}, language = {en} } @article{RickmanLachAbhyankaretal.2015, author = {Rickman, Kimberly A. and Lach, Francis P. and Abhyankar, Avinash and Donovan, Frank X. and Sanborn, Erica M. and Kennedy, Jennifer A. and Sougnez, Carrie and Gabriel, Stacey B. and Elemento, Olivier and Chandrasekharappa, Settara C. and Schindler, Detlev and Auerbach, Arleen D. and Smogorzewska, Agata}, title = {Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia}, series = {Cell Reports}, volume = {12}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2015.06.014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151525}, pages = {35 -- 41}, year = {2015}, abstract = {Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.}, language = {en} } @article{UrbanRemmeleDittrichetal.2020, author = {Urban, Lara and Remmele, Christian W. and Dittrich, Marcus and Schwarz, Roland F. and M{\"u}ller, Tobias}, title = {covRNA: discovering covariate associations in large-scale gene expression data}, series = {BMC Reserach Notes}, volume = {13}, journal = {BMC Reserach Notes}, doi = {10.1186/s13104-020-04946-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229258}, year = {2020}, abstract = {Objective The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the intrinsic correlation structure of complex annotated gene expression data and discover the covariates that jointly affect expression patterns. Results The Bioconductor package covRNA provides a convenient and fast interface for testing and visualizing complex relationships between sample and gene covariates mediated by gene expression data in an entirely unsupervised setting. The relationships between sample and gene covariates are tested by statistical permutation tests and visualized by ordination. The methods are inspired by the fourthcorner and RLQ analyses used in ecological research for the analysis of species abundance data, that we modified to make them suitable for the distributional characteristics of both, RNA-Seq read counts and microarray intensities, and to provide a high-performance parallelized implementation for the analysis of large-scale gene expression data on multi-core computational systems. CovRNA provides additional modules for unsupervised gene filtering and plotting functions to ensure a smooth and coherent analysis workflow.}, language = {en} } @article{VonaHofrichterSchroederetal.2018, author = {Vona, Barbara and Hofrichter, Michaela A. H. and Schr{\"o}der, J{\"o}rg and Shehata-Dieler, Wafaa and Nanda, Indrajit and Haaf, Thomas}, title = {Hereditary hearing loss SNP-microarray pilot study}, series = {BMC Research Notes}, volume = {11}, journal = {BMC Research Notes}, number = {391}, doi = {10.1186/s13104-018-3466-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176239}, year = {2018}, abstract = {Objectives: Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of copy number variation that can be mapped using SNP-microarray technology. A growing collection of literature has begun to uncover the importance of copy number variation in hereditary hearing loss. This pilot study underpins a larger effort that involves the stage-wise analysis of hearing loss patients, many of whom have advanced to high-throughput sequencing analysis. Data description: Our data originate from the Infinium HumanOmni1-Quad v1.0 SNP-microarrays (Illumina) that provide useful markers for genome-wide association studies and copy number variation analysis. This dataset comprises a cohort of 108 individuals (99 with hearing loss, 9 normal hearing family members) for the purpose of understanding the genetic contribution of copy number variations to hereditary hearing loss. These anonymized SNP-microarray data have been uploaded to the NCBI Gene Expression Omnibus and are intended to benefit other investigators interested in aggregating platform-matched array patient datasets or as part of a supporting reference tool for other laboratories to better understand recurring copy number variations in other genetic disorders.}, language = {en} } @article{ZieglerRadtkeVitaleetal.2021, author = {Ziegler, Georg C. and Radtke, Franziska and Vitale, Maria Rosaria and Preuße, Andr{\´e} and Klopocki, Eva and Herms, Stefan and Lesch, Klaus-Peter}, title = {Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers}, series = {Stem Cell Research}, volume = {56}, journal = {Stem Cell Research}, doi = {10.1016/j.scr.2021.102526}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264696}, year = {2021}, abstract = {Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries.}, language = {en} }