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1. A case of an Angelman-syndrome caused by an intragenic duplication of UBE3A uncovered by adaptive nanopore sequencing

Author: Laura Holthöfer, Stefan Diederich, Verena Haug, Lioba Lehmann, Charlotte Hewel, Norbert W. Paul, Susann Schweiger, Susanne Gerber, and Matthias Linke
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM_000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders.
Published: 2024
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2. SARS-CoV-2 surveillance in a hospital and control of an outbreak on a geriatric ward using whole genome sequencing

Author: Hanno Schmidt, Niels Lemmermann, Matthias Linke, Sven-Ernö Bikár, Stefan Runkel, Susann Schweiger-Seemann, Susanne Gerber, André Michel, Thomas Hankeln, Marina Veith, Wolfgang Kohnen, and Bodo Plachter
Subjects: SARS-CoV-2, Whole genome sequencing, Variant monitoring, Covid-19, Hygiene management, Infectious and parasitic diseases, RC109-216, Public aspects of medicine, RA1-1270
Abstract: Summary: Background: During the SARS-CoV-2 pandemic, dominant viral variants were repeatedly replaced by new variants with altered properties, frequently changing the dynamics of the infection event, as well as the effectiveness of vaccines and therapeutics. SARS-CoV-2 variant monitoring by whole genome sequencing was established at the University Medical Center Mainz, Germany to support patient management during the pandemic. Methods: SARS-CoV-2 RNA samples from the University Medical Center were analysed weekly with whole genome sequencing. The genome sequences obtained were aligned with sequences from public databases to perform variant assignment. For classification purposes, phylogenetic trees were constructed to map the variant distribution in the clinical settings and the current outbreak events at that time. We describe the surveillance procedures using an example from a geriatric ward. Results: For monitoring, a time series was created covering two years of the pandemic. The changes from the Alpha to the Delta and the Omicron variants of SARS-CoV-2 could thus be precisely observed. The increasingly rapid switch of Omicron subvariants in the recent past could be tracked. The elucidation of phylogenetic relationships between circulating strains allowed conclusions about transmission pathways. Using an example from a geriatric ward, we demonstrated how variant monitoring by whole genome sequencing supported the infection prevention and control procedures on a ward and contribute to the control of outbreaks. Conclusions: This example of SARS-CoV-2 demonstrates the effectiveness of targeted, local monitoring by molecular variant analysis. The program proved to be instrumental in controlling an outbreak on a geriatric ward.
Published: 2024
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3. Effect of the addition of a mental health specialist for evaluation of undiagnosed patients in centres for rare diseases (ZSE-DUO): a prospective, controlled trial with a two-phase cohort designResearch in context

Author: Helge Hebestreit, Anne-Marie Lapstich, Lilly Brandstetter, Christian Krauth, Jürgen Deckert, Kirsten Haas, Lisa Pfister, Stefanie Witt, Christopher Schippers, Jan Dieris-Hirche, Tim Maisch, Oliver Tüscher, Lavinia Bârlescu, Alexandra Berger, Mark Berneburg, Vanessa Britz, Anna Deibele, Holm Graeßner, Harald Gündel, Gereon Heuft, Thomas Lücke, Christine Mundlos, Julia Quitmann, Frank Rutsch, Katharina Schubert, Jörg Bernhard Schulz, Susann Schweiger, Cornelia Zeidler, Lena Zeltner, Martina de Zwaan, Federica Akkaya, Christine Babka, Lisa Bannert, Anja Bärsch-Michelmann, Leonie Böhm, Folke Brinkmann, Monika Bullinger, Holger Cario, Moritz de Greck, Klaus-Michael Debatin, Katrin Dillmann-Jehn, Jutta Eymann, Julia Frisch, Anja Glode, Vega Gödecke, Corinna Grasemann, Eva Grauer, Astrid Haas, Lea Haisch, Isabell, Heinrich, Melissa Held, Julia Hennermann, Stephan Herpertz, Anne Herrmann-Werner, Julian Hett, Peter Heuschmann, Bettina Hilbig, Laura Holthöfer, Christiane Imhof, Florian Junne, Jan Kassubek, Kevin-Thomas Koschitzki, Heike Krassort, Birgit Kropff, Julia Kuhn, Philipp Latzko, Thomas Loew, Albert C. Ludolph, Torsten Meyer, Isabell Meyer dos Santos, Klaus Mohnike, Martina Monninger, Martin Mücke, Susanne Müller, Thomas Musacchio, Margret Nießen, Mariel Nöhre, Stephan Ott, Andrea Petermann-Meyer, Christina Pfeifer-Duck, Lea-Sophie Piduhn, Carina Rampp, Olaf Rieß, Kristina Schaubert, Annika Schmidt, Simone Schneider, Ludger Schoels, Martina Schwalba, Udo Selig, Alexandra Sroka, Toni Steinbüchel, Sebastian Stösser, Steffi Suchant, Kathrin Ungethüm, Matthias Vogel, Daniela Volk, Christoph Vollmuth, Solange Volnov, Thomas O.F. Wagner, Sabrina Walter, Bodo Warrings, Kamil Zajt, Karola Zenker, David Zhang, Stephan Zipfel, Lavinia Aurelia Bârlescu, Julia Hannah Quitmann, Jörg B. Schulz, and Lena Margarete Zeltner
Subjects: Rare diseases, Diagnostic services, Mental health, Patient care team, Medically unexplained symptoms, Medicine (General), R5-920
Abstract: Summary: Background: People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome. Methods: Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N = 684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N = 695). The cohorts consisted mainly of adult participants with only a minority of children included (N = 67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677. Findings: The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N = 131 of 672) in the SC and 42% (N = 286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99–5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1–2), and significantly more patients could be referred to local regular care in the IC (27.5%; N = 181 of 659) compared to the SC (12.3%; N = 81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02–3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts. Interpretation: Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease. Funding: The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031.
Published: 2023
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4. Childhood glaucoma registry in Germany: initial database, clinical care and research (pilot study)

Author: Fidan A. Aghayeva, Alexander K. Schuster, Heidi Diel, Panagiotis Chronopoulos, Felix M. Wagner, Franz Grehn, Nina Pirlich, Susann Schweiger, Norbert Pfeiffer, and Esther M. Hoffmann
Subjects: Childhood glaucoma registry, Congenital glaucoma, Consanguinity, Genetic examination, Questionnaire, Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract: Abstract Objective The aim of this prospective pilot study is to establish an initial database to register patients diagnosed with different types of childhood glaucoma and the set-up of a national registry for childhood glaucoma (ReCG) in Germany. 28 children with different types of diagnosed childhood glaucoma, who were admitted and treated at the Childhood Glaucoma Center of the University Medical Center Mainz, Germany were included. Main outcome measures were the type of childhood glaucoma, mean intraocular pressure (IOP) and genetic data of the patients. Results The documents and questionnaires for each individual included: informed consent form of the parents, medical history form of the child, patient’s gestational history questionnaire and general anesthesia examination form. Primary congenital and secondary childhood glaucoma were revealed in 11 (39%) and 17 (61%) patients, respectively. The mean IOP measured with Perkins tonometer in all patients under general anesthesia at the time of inclusion was 17.5 ± 11.8 mmHg in the right and 17 ± 8.9 mmHg in the left eyes. In 33% of children with glaucoma mutations in the CYP1B1, FOXC1, LTBP2 and TEK genes were found. The development of specific questionnaires for childhood glaucoma provides detailed baseline data to establish a ReCG in Germany for the first time.
Published: 2022
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5. Dual guidance structure for evaluation of patients with unclear diagnosis in centers for rare diseases (ZSE-DUO): study protocol for a controlled multi-center cohort study

Author: Helge Hebestreit, Cornelia Zeidler, Christopher Schippers, Martina de Zwaan, Jürgen Deckert, Peter Heuschmann, Christian Krauth, Monika Bullinger, Alexandra Berger, Mark Berneburg, Lilly Brandstetter, Anna Deibele, Jan Dieris-Hirche, Holm Graessner, Harald Gündel, Stephan Herpertz, Gereon Heuft, Anne-Marie Lapstich, Thomas Lücke, Tim Maisch, Christine Mundlos, Andrea Petermann-Meyer, Susanne Müller, Stephan Ott, Lisa Pfister, Julia Quitmann, Marcel Romanos, Frank Rutsch, Kristina Schaubert, Katharina Schubert, Jörg B. Schulz, Susann Schweiger, Oliver Tüscher, Kathrin Ungethüm, Thomas O. F. Wagner, Kirsten Haas, and ZSE-DUO working group
Subjects: Rare diseases, Undetermined symptoms, Unclear diagnosis, Mental health disorders, Cohort study, Medicine
Abstract: Abstract Background In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process. Study design This multi-center, prospective controlled study has a two-phase cohort design. Methods Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2). Outcomes Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach. Conclusions This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease. Trial registration ClinicalTrials.gov; Identifier: NCT03563677; First posted: June 20, 2018, https://clinicaltrials.gov/ct2/show/NCT03563677 .
Published: 2022
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6. The Big Picture of Neurodegeneration: A Meta Study to Extract the Essential Evidence on Neurodegenerative Diseases in a Network-Based Approach

Author: Nicolas Ruffini, Susanne Klingenberg, Raoul Heese, Susann Schweiger, and Susanne Gerber
Subjects: neurodegenerative diseases, metastudy, multi-omic analyses, bioinformatics, hub genes and pathways, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: The common features of all neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease, are the accumulation of aggregated and misfolded proteins and the progressive loss of neurons, leading to cognitive decline and locomotive dysfunction. Still, they differ in their ultimate manifestation, the affected brain region, and the kind of proteinopathy. In the last decades, a vast number of processes have been described as associated with neurodegenerative diseases, making it increasingly harder to keep an overview of the big picture forming from all those data. In this meta-study, we analyzed genomic, transcriptomic, proteomic, and epigenomic data of the aforementioned diseases using the data of 234 studies in a network-based approach to study significant general coherences but also specific processes in individual diseases or omics levels. In the analysis part, we focus on only some of the emerging findings, but trust that the meta-study provided here will be a valuable resource for various other researchers focusing on specific processes or genes contributing to the development of neurodegeneration.
Published: 2022
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7. Reliability of genomic variants across different next-generation sequencing platforms and bioinformatic processing pipelines

Author: Stephan Weißbach, Stanislav Sys, Charlotte Hewel, Hristo Todorov, Susann Schweiger, Jennifer Winter, Markus Pfenninger, Ali Torkamani, Doug Evans, Joachim Burger, Karin Everschor-Sitte, Helen Louise May-Simera, and Susanne Gerber
Subjects: Next-generation sequencing (NGS) technologies, Platform-biases, Healthy aging, Illumina, Wellderly, Longevity, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract: Abstract Background Next Generation Sequencing (NGS) is the fundament of various studies, providing insights into questions from biology and medicine. Nevertheless, integrating data from different experimental backgrounds can introduce strong biases. In order to methodically investigate the magnitude of systematic errors in single nucleotide variant calls, we performed a cross-sectional observational study on a genomic cohort of 99 subjects each sequenced via (i) Illumina HiSeq X, (ii) Illumina HiSeq, and (iii) Complete Genomics and processed with the respective bioinformatic pipeline. We also repeated variant calling for the Illumina cohorts with GATK, which allowed us to investigate the effect of the bioinformatics analysis strategy separately from the sequencing platform’s impact. Results The number of detected variants/variant classes per individual was highly dependent on the experimental setup. We observed a statistically significant overrepresentation of variants uniquely called by a single setup, indicating potential systematic biases. Insertion/deletion polymorphisms (indels) were associated with decreased concordance compared to single nucleotide polymorphisms (SNPs). The discrepancies in indel absolute numbers were particularly prominent in introns, Alu elements, simple repeats, and regions with medium GC content. Notably, reprocessing sequencing data following the best practice recommendations of GATK considerably improved concordance between the respective setups. Conclusion We provide empirical evidence of systematic heterogeneity in variant calls between alternative experimental and data analysis setups. Furthermore, our results demonstrate the benefit of reprocessing genomic data with harmonized pipelines when integrating data from different studies.
Published: 2021
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8. Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome

Author: Alexis Cooper, Tamer Butto, Niklas Hammer, Somanath Jagannath, Desiree Lucia Fend-Guella, Junaid Akhtar, Konstantin Radyushkin, Florian Lesage, Jennifer Winter, Susanne Strand, Jochen Roeper, Ulrich Zechner, and Susann Schweiger
Subjects: Science
Abstract: Birk-Barel intellectual disability is an imprinting syndrome due to maternally-only transmitted mutations of KCNK9/TASK3. Here authors are using a heterozygous deletion of the active maternal Kcnk9 allele to model the disease and show phenotypic rescue by HDAC inhibition.
Published: 2020
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9. A Resilience Related Glial-Neurovascular Network Is Transcriptionally Activated after Chronic Social Defeat in Male Mice

Author: Constance Vennin, Charlotte Hewel, Hristo Todorov, Marlon Wendelmuth, Konstantin Radyushkin, André Heimbach, Illia Horenko, Sarah Ayash, Marianne B. Müller, Susann Schweiger, Susanne Gerber, and Beat Lutz
Subjects: single-cell RNA-seq, stress resilience, hippocampus, neuroimmune pathways, cell-cell interaction, glial cells, Cytology, QH573-671
Abstract: Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of the hippocampus in a mouse model of chronic social defeat stress. Our work revealed that in a sub-group exhibiting molecular responses upon chronic stress, the dorsal hippocampus is particularly involved in neuroimmune responses, angiogenesis, myelination, and neurogenesis, thereby enabling brain restoration and homeostasis after chronic stress. Based on these molecular insights, we applied rapamycin after the stress as a proof-of-concept pharmacological intervention and were able to substantially increase stress resilience. Our findings serve as a data resource and can open new avenues for further understanding of molecular processes underlying stress response and for targeted interventions supporting resilience.
Published: 2022
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10. 18F-FDG PET/CT: an unexpected case of Huntington’s disease

Author: Sebastian Michels, Hans-Georg Buchholz, Florian Rosar, Isabel Heinrich, Manuela A. Hoffmann, Susann Schweiger, Oliver Tüscher, and Mathias Schreckenberger
Subjects: Huntington’s disease, FDG-PET/CT, Striatal hypometabolism, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Huntington’s disease (HD) is a rare, genetic neurodegenerative disorder often presenting with emotional, cognitive and behavioral abnormalities before manifestation of disease defining motor symptoms. Cognitive impairment is a frequent clinical feature caused by different dementia subtypes. Imaging cortical and subcortical glucose metabolism via 18F-FDG PET/CT can help to discriminate the underlying disease. Case presentation The patient is a 54-year old man presenting with progressive cognitive impairment and mild orofacial dyskinesia. 18F-FDG PET/CT of the brain revealed a severe bilateral hypometabolism in the striatum. Following imaging Huntington’s disease was suspected and a molecular genetic testing confirmed the diagnosis. Conclusions Huntington’s disease is a rare but important differential diagnosis of cognitive impairment, especially before motor symptoms are manifest. 18F-FDG PET is capable to show early striatal dysfunction in HD even when structural imaging is normal. We conclude that, in cases with negative family history the HD characteristic metabolic pattern can lead to the diagnosis when no other dementia-suspected changes are present.
Published: 2019
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11. Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

Author: Katalin Komlosi, Stefan Diederich, Desiree Lucia Fend-Guella, Oliver Bartsch, Jennifer Winter, Ulrich Zechner, Michael Beck, Peter Meyer, and Susann Schweiger
Subjects: next generation sequencing, panel diagnostics, consanguineous, carrier screening, autosomal recessive, Medicine
Abstract: Abstract Background Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. Methods We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. Results The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. Conclusions For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions.
Published: 2018
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12. RNA stability controlled by m6A methylation contributes to X-to-autosome dosage compensation in mammals

Author: Cornelia Rücklé, Nadine Körtel, M. Felicia Basilicata, Anke Busch, You Zhou, Peter Hoch-Kraft, Kerstin Tretow, Fridolin Kielisch, Marco Bertin, Mihika Pradhan, Michael Musheev, Susann Schweiger, Christof Niehrs, Oliver Rausch, Kathi Zarnack, Claudia Isabelle Keller Valsecchi, and Julian König
Subjects: Structural Biology, Molecular Biology
Abstract: In mammals, X-chromosomal genes are expressed from a single copy since males (XY) possess a single X chromosome, while females (XX) undergo X inactivation. To compensate for this reduction in dosage compared with two active copies of autosomes, it has been proposed that genes from the active X chromosome exhibit dosage compensation. However, the existence and mechanisms of X-to-autosome dosage compensation are still under debate. Here we show that X-chromosomal transcripts have fewer m6A modifications and are more stable than their autosomal counterparts. Acute depletion of m6A selectively stabilizes autosomal transcripts, resulting in perturbed dosage compensation in mouse embryonic stem cells. We propose that higher stability of X-chromosomal transcripts is directed by lower levels of m6A, indicating that mammalian dosage compensation is partly regulated by epitranscriptomic RNA modifications.
Published: 2023

13. mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex

Author: Martin Schüle, Tamer Butto, Sri Dewi, Laura Schlichtholz, Susanne Strand, Susanne Gerber, Kristina Endres, Susann Schweiger, and Jennifer Winter
Subjects: mTOR, mTORC1, cholesterol, neurogenesis, SREBP, SP1, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders (ASD) to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy, and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood. Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1, and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels, pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.
Published: 2021
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14. Supplementary Figure 3 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Rainer Schneider, John Foerster, and Sybille Krauß
Abstract: Supplementary Figure 3 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
Published: 2023

15. Supplementary Tables 1-5 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Rainer Schneider, John Foerster, and Sybille Krauß
Abstract: Supplementary Tables 1-5 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
Published: 2023

16. Supplementary Figure 2 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Rainer Schneider, John Foerster, and Sybille Krauß
Abstract: Supplementary Figure 2 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
Published: 2023

17. Data from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Rainer Schneider, John Foerster, and Sybille Krauß
Abstract: Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, α4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin. [Cancer Res 2008;68(12):4658–65]
Published: 2023

18. Supplementary Legends for Figures 1-3, Tables 1-5 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Rainer Schneider, John Foerster, and Sybille Krauß
Abstract: Supplementary Legends for Figures 1-3, Tables 1-5 from Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3
Published: 2023

19. Common Factors in Neurodegeneration: A Meta-Study Revealing Shared Patterns on a Multi-Omics Scale

Author: Nicolas Ruffini, Susanne Klingenberg, Susann Schweiger, and Susanne Gerber
Subjects: multi-omics, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, neurodegeneration, Cytology, QH573-671
Abstract: Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are heterogeneous, progressive diseases with frequently overlapping symptoms characterized by a loss of neurons. Studies have suggested relations between neurodegenerative diseases for many years (e.g., regarding the aggregation of toxic proteins or triggering endogenous cell death pathways). We gathered publicly available genomic, transcriptomic, and proteomic data from 177 studies and more than one million patients to detect shared genetic patterns between the neurodegenerative diseases on three analyzed omics-layers. The results show a remarkably high number of shared differentially expressed genes between the transcriptomic and proteomic levels for all conditions, while showing a significant relation between genomic and proteomic data between AD and PD and AD and ALS. We identified a set of 139 genes being differentially expressed in several transcriptomic experiments of all four diseases. These 139 genes showed overrepresented gene ontology (GO) Terms involved in the development of neurodegeneration, such as response to heat and hypoxia, positive regulation of cytokines and angiogenesis, and RNA catabolic process. Furthermore, the four analyzed neurodegenerative diseases (NDDs) were clustered by their mean direction of regulation throughout all transcriptomic studies for this set of 139 genes, with the closest relation regarding this common gene set seen between AD and HD. GO-Term and pathway analysis of the proteomic overlap led to biological processes (BPs), related to protein folding and humoral immune response. Taken together, we could confirm the existence of many relations between Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis on transcriptomic and proteomic levels by analyzing the pathways and GO-Terms arising in these intersections. The significance of the connection and the striking relation of the results to processes leading to neurodegeneration between the transcriptomic and proteomic data for all four analyzed neurodegenerative diseases showed that exploring many studies simultaneously, including multiple omics-layers of different neurodegenerative diseases simultaneously, holds new relevant insights that do not emerge from analyzing these data separately. Furthermore, the results shed light on processes like the humoral immune response that have previously been described only for certain diseases. Our data therefore suggest human patients with neurodegenerative diseases should be addressed as complex biological systems by integrating multiple underlying data sources.
Published: 2020
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20. Added Value of a Mental Health Specialist for Evaluation of Undiagnosed Patients in Centres for Rare Diseases – The ZSE-DUO Cohort Study

Author: Helge Hebestreit, Anne-Marie Lapstich, Lilly Brandstetter, Christian Krauth, Jürgen Deckert, Kirsten Haas, Lisa Pfister, Stefanie Witt, Christopher Schippers, Jan Dieris-Hirche, Tim Maisch, Oliver Tüscher, Lavinia Bârlescu, Alexandra Berger, Mark Berneburg, Vanessa Britz, Anna Deibele, Holm Graessner, Harald Gündel, Gereon Heuft, Thomas Lücke, Christine Mundlos, Julia Hannah Quitmann, Frank Rutsch, Katharina Schubert, Jörg B. Schulz, Susann Schweiger, Cornelia Zeidler, Lena Margarete Zeltner, and Martina DeZwaan
Published: 2023

21. Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

Author: Isabelle Arnoux, Michael Willam, Nadine Griesche, Jennifer Krummeich, Hirofumi Watari, Nina Offermann, Stephanie Weber, Partha Narayan Dey, Changwei Chen, Olivia Monteiro, Sven Buettner, Katharina Meyer, Daniele Bano, Konstantin Radyushkin, Rosamund Langston, Jeremy J Lambert, Erich Wanker, Axel Methner, Sybille Krauss, Susann Schweiger, and Albrecht Stroh
Subjects: Huntington disease, in vivo calcium imaging, cortical microcircuits, neuronal hyperactivity, metformin, Medicine, Science, Biology (General), QH301-705.5
Abstract: Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.
Published: 2018
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22. A Rapamycin-Inducible Glial-Neurovascular Network Promotes Adaptation after Chronic Social Defeat

Author: Constance Vennin, Charlotte Hewel, Hristo Todorov, Marlon Wendelmuth, Konstantin Radyushkin, Andre Heimbach, Illia Horenko, Sarah Ayash, Marianne B. Müller, Susann Schweiger, Gerber Susanne, and Beat Lutz
Published: 2022

23. Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Author: Aet O’Leary, Noèlia Fernàndez-Castillo, Gabriela Gan, Yunbo Yang, Anna Y. Yotova, Thorsten M. Kranz, Lena Grünewald, Florian Freudenberg, Ester Antón-Galindo, Judit Cabana-Domínguez, Anais Harneit, Janina I. Schweiger, Kristina Schwarz, Ren Ma, Junfang Chen, Emanuel Schwarz, Marcella Rietschel, Heike Tost, Andreas Meyer-Lindenberg, Christiane A. Pané-Farré, Tilo Kircher, Alfons O. Hamm, Demian Burguera, Nina Roth Mota, Barbara Franke, Susann Schweiger, Jennifer Winter, Andreas Heinz, Susanne Erk, Nina Romanczuk-Seiferth, Henrik Walter, Andreas Ströhle, Lydia Fehm, Thomas Fydrich, Ulrike Lueken, Heike Weber, Thomas Lang, Alexander L. Gerlach, Markus M. Nöthen, Georg W. Alpers, Volker Arolt, Stephanie Witt, Jan Richter, Benjamin Straube, Bru Cormand, David A. Slattery, and Andreas Reif
Subjects: Neurons, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Mental illness, RNA, Neurones, Malalties mentals, Molecular Biology
Abstract: Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.
Published: 2022
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24. First Results from the Prospective German Registry for Childhood Glaucoma: Phenotype–Genotype Association

Author: Julia V. Stingl, Stefan Diederich, Heidi Diel, Alexander K. Schuster, Felix M. Wagner, Panagiotis Chronopoulos, Fidan Aghayeva, Franz Grehn, Jennifer Winter, Susann Schweiger, and Esther M. Hoffmann
Subjects: genetic structures, genotype phenotype correlation, General Medicine, eye diseases, Article, molecular genetic analysis, consanguinity, childhood glaucoma, primary congenital glaucoma, CYP1B1, Medicine, sense organs
Abstract: Childhood glaucoma is a heterogeneous disease and can be associated with various genetic alterations. The aim of this study was to report first results of the phenotype–genotype relationship in a German childhood glaucoma cohort. Forty-nine eyes of 29 children diagnosed with childhood glaucoma were prospectively included in the registry. Besides medical history, non-genetic risk factor anamnesis and examination results, genetic examination report was obtained (23 cases). DNA from peripheral blood or buccal swab was used for molecular genetic analysis using a specific glaucoma gene panel. Primary endpoint was the distribution of causative genetic mutations and associated disorders. Median age was 1.8 (IQR 0.6; 3.8) years, 64% participants were female. Secondary childhood glaucoma (55%) was more common than primary childhood glaucoma (41%). In 14%, parental consanguinity was indicated. A mutation was found in all these cases, which makes consanguinity an important risk factor for genetic causes in childhood glaucoma. CYP1B1 (30%) and TEK (10%) mutations were found in primary childhood glaucoma patients. In secondary childhood glaucoma cases, alterations in CYP1B1 (25%), SOX11 (13%), FOXC1 (13%), GJA8 (13%) and LTBP2 (13%) were detected. Congenital cataract was associated with variants in FYCO1 and CRYBB3 (25% each), and one case of primary megalocornea with a CHRDL1 aberration. Novel variants of causative genetic mutations were found. Distribution of childhood glaucoma types and causative genes was comparable to previous investigated cohorts. This is the first prospective study using standardized forms to determine phenotypes and non-genetic factors in childhood glaucoma with the aim to evaluate their association with genotypes in childhood glaucoma.
Published: 2021

25. Dual Guidance Structure for Evaluation of Patients with Unclear Diagnosis in Centers for Rare Diseases (ZSE-DUO): Study Protocol for a Controlled Multi-center Cohort Study

Author: Helge, Hebestreit, Cornelia, Zeidler, Christopher, Schippers, Martina, de Zwaan, Jürgen, Deckert, Peter, Heuschmann, Christian, Krauth, Monika, Bullinger, Alexandra, Berger, Mark, Berneburg, Lilly, Brandstetter, Anna, Deibele, Jan, Dieris-Hirche, Holm, Graessner, Harald, Gündel, Stephan, Herpertz, Gereon, Heuft, Anne-Marie, Lapstich, Thomas, Lücke, Tim, Maisch, Christine, Mundlos, Andrea, Petermann-Meyer, Susanne, Müller, Stephan, Ott, Lisa, Pfister, Julia, Quitmann, Marcel, Romanos, Frank, Rutsch, Kristina, Schaubert, Katharina, Schubert, Jörg B, Schulz, Susann, Schweiger, Oliver, Tüscher, Kathrin, Ungethüm, Thomas O F, Wagner, Kirsten, Haas, Stephan, Zipfel, Rampp, Carina, Richter, Antonia, Rieß, Olaf, Schmidt, Annika, Schneider, Simone, Schoels, Ludger, Schwalba, Martina, Selig, Udo, Spangenberger, Astrid, Sroka, Alexandra, Steinbüchel, Toni, Stösser, Sebastian, Suchant, Steffi, Vogel, Matthias, Volk, Daniela, Vollmuth, Christoph, Volnov, Solange, Walter, Sabrina, Warrings, Bodo, Weiler, Christine, Witt, Stefanie, Zajt, Kamil Kajetan, Zeltner, Lena, Zenker, Karola, Zhang, Kailun David, Zipfel, Stephan, Akkaya, Federica, Babka, Christine, Bârlescu, Lavinia, Bärsch-Michelmann, Anja, Bergbreiter, Astrid, Blömeke, Janika, Böhm, Leonie, Böttger, Benita, Braun, Birgit, Brinkmann, Folke, Britz, Vanessa, Cario, Holger, Celiker, Melisa, de Greck, Moritz, Debatin, Klaus-Michael, Dillmann-Jehn, Katrin, Ertl, Max, Ettinger, Monika, Eymann, Jutta, Frommer, Jörg, Gabrian, Martina, Glode, Anja, Gödecke, Vega, Grasemann, Corinna, Grauer, Eva, Greger, Helmut, Haas, Astrid, Haase, Martina, Haisch, Lea, Heinrich, Isabel, Held, Melissa, Hennermann, Julia, Herrmann-Werner, Anne, Hett, Julian, Hilbig, Bettina, Holthöfer, Laura, Imhof, Christiane, Jacob, Titus, Junne, Florian, Karl, Stefanie, Kassubek, Jan, Kick, Lisa, Koschitzki, Kevin-Thomas, Krassort, Heike, Kratz, Christian, Kristensen, Kaja, Kropff, Birgit, Kuhn, Julia, Latzko, Philipp, Loew, Thomas, Lorenz, Delia, Ludolph, Albert C., Dos Santos, Isabell Meyer, Meyer, Torsten, Mohnike, Klaus, Monninger, Martina, Musacchio, Thomas, Nanciu, Amalia Nicole, Nießen, Margret, Nöhre, Mariell, Papagianni, Aikaterini, Pfeifer-Duck, Christina, and Piduhn, Lea-Sophie
Subjects: Protocol (science), medicine.medical_specialty, ddc:618, business.industry, General Medicine, DUAL (cognitive architecture), Cohort Studies, Diagnosis, Differential, Rare Diseases, Treatment Outcome, Quality of Life, Humans, Multicenter Studies as Topic, Medicine, Pharmacology (medical), Medical physics, Center (algebra and category theory), Prospective Studies, Child, business, Genetics (clinical), Cohort study
Abstract: Orphanet journal of rare diseases : OJRD 17(1), 47 (2022). doi:10.1186/s13023-022-02176-1, Published by BioMed Central, London
Published: 2021

26. mTOR Driven Gene Transcription Is Required for Cholesterol Production in Neurons of the Developing Cerebral Cortex

Author: Tamer Butto, Martin Schüle, Jennifer Winter, Kristina Endres, Susanne Strand, Susanne Gerber, Sri Dewi, Laura Schlichtholz, and Susann Schweiger
Subjects: Transcription, Genetic, QH301-705.5, Primary Cell Culture, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, SREBP, Catalysis, Article, Inorganic Chemistry, Mice, Autophagy, Transcriptional regulation, medicine, Animals, Physical and Theoretical Chemistry, Biology (General), Molecular Biology, Transcription factor, QD1-999, Spectroscopy, PI3K/AKT/mTOR pathway, Cerebral Cortex, Neurons, Sterol Regulatory Element Binding Proteins, Cell growth, TOR Serine-Threonine Kinases, Organic Chemistry, cholesterol, NF-Y, neurogenesis, mTOR, SP1, Gene Expression Regulation, Developmental, General Medicine, Computer Science Applications, Sterol regulatory element-binding protein, Cell biology, Chemistry, medicine.anatomical_structure, CCAAT-Binding Factor, Cerebral cortex, Protein Kinases, Signal Transduction
Abstract: Dysregulated mammalian target of rapamycin (mTOR) activity is associated with various neurodevelopmental disorders ranging from idiopathic autism spectrum disorders to syndromes caused by single gene defects. This suggests that maintaining mTOR activity levels in a physiological range is essential for brain development and functioning. Upon activation, mTOR regulates a variety of cellular processes such as cell growth, autophagy and metabolism. On a molecular level, however, the consequences of mTOR activation in the brain are not well understood.Low levels of cholesterol are associated with a wide variety of neurodevelopmental disorders. We here describe numerous genes of the sterol/cholesterol biosynthesis pathway to be transcriptionally regulated by mTOR complex 1 (mTORC1) signaling in vitro in primary neurons and in vivo in the developing cerebral cortex of the mouse. We find that these genes are shared targets of the transcription factors SREBP, SP1 and NF-Y. Prenatal as well as postnatal mTORC1 inhibition downregulated expression of these genes which directly translated into reduced cholesterol levels pointing towards a substantial metabolic function of the mTORC1 signaling cascade. Altogether, our results indicate that mTORC1 is an essential transcriptional regulator of the expression of sterol/cholesterol biosynthesis genes in the developing brain. Altered expression of these genes may be an important factor contributing to the pathogenesis of neurodevelopmental disorders associated with dysregulated mTOR signaling.
Published: 2021
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27. Results of childhood glaucoma surgery over a long-term period

Author: Esther M. Hoffmann, Mona Karsten, Fidan Aghayeva, Felix M Wagner, Franz Grehn, Alexander K. Schuster, Norbert Pfeiffer, Susann Schweiger, Nina Pirlich, and Panagiotis Chronopoulos
Subjects: Male, Intraocular pressure, medicine.medical_specialty, genetic structures, Adolescent, medicine.medical_treatment, Glaucoma, Trabeculectomy, Childhood glaucoma, Glaucoma surgery, Medicine, Humans, Patient group, Child, Intraocular Pressure, Retrospective Studies, Surgical approach, business.industry, Secondary glaucoma, Infant, Newborn, Infant, General Medicine, medicine.disease, Trabeculotomy, eye diseases, Surgery, Ophthalmology, Treatment Outcome, Child, Preschool, Female, sense organs, business
Abstract: Purpose To evaluate long-term results of glaucoma surgery in newborn and infants with glaucoma. Methods Seventy-nine eyes of 52 children (age: 3 weeks-15.3 years) with primary congenital or secondary glaucoma treated between 2015 and 2017 were included. The median follow-up time was 3.9 years. Conventional probe trabeculotomy, 360° catheter-assisted trabeculotomy, filtering and cyclodestructive surgery were compared. Strict criteria for surgical success were applied: Complete surgical success (IOP below target IOP, no further surgery) and incomplete surgical success (additional surgery allowed) were analyzed, and IOP at baseline and last follow-up was compared. Results Intraocular pressure (IOP) was significantly reduced in primary congenital (preoperative IOP: 27.8 ± 7.5 mmHg vs. postoperative IOP: 14.2 ± 4.5 mmHg) and secondary glaucoma (preoperative IOP: 29.2 ± 9.1 mmHg vs. postoperative IOP: 16.6 ± 4.7 mmHg). 90% of all eyes reached target IOP with or without medication allowing for additional surgeries. As first surgery, 360° catheter-assisted trabeculotomy had a tendency to higher surgical success than other surgical approaches, while cyclodestructive procedures had lowest. Conclusions We found very promising surgical results in our childhood glaucoma patient group. Surgical success in both congenital and secondary glaucoma was high.
Published: 2021

28. SARS-CoV-2 genome surveillance in Mainz, Germany, reveals convergent origin of the N501Y spike mutation in a hospital setting

Author: Anastasija Michel, Susanne Gerber, Niels A. W. Lemmermann, Susann Schweiger, Stefan Runkel, Angélique Renzaho, Kohnen W, Laufs T, Lieb B, Linke M, Thomas Hankeln, Bodo Plachter, and Bikar S
Subjects: Genetics, Convergent evolution, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Viral evolution, Genotype, Mutation (genetic algorithm), Spike (database), Biology, Genome, DNA sequencing
Abstract: While establishing a regional SARS-Cov-2 variant surveillance by genome sequencing, we have identified three infected individuals in a clinical setting (two long-term hospitalized patients and a nurse) that shared the spike N501Y mutation within a genotype background distinct from the current viral variants of concern. We suggest that the adaptive N501Y mutation, known to increase SARS-CoV-2 transmissibility, arose by convergent evolution around December in Mainz, Germany. Hospitalized patients with a compromised immune system may be a potential source of novel viral variants, which calls for monitoring viral evolution by genome sequencing in clinical settings.
Published: 2021

29. Reliability of genomic variants across different next-generation sequencing platforms and bioinformatic processing pipelines

Author: Stephan Weißbach, Stanislav Jur`Evic Sys, Charlotte Hewel, Hristo Todorov, Susann Schweiger, Jennifer Winter, Markus Pfenninger, Ali Torkamani, Doug Evans, Joachim Burger, Karin Everschor-Sitte, Helen May-Simera, and Susanne Gerber
Subjects: Aging, lcsh:QH426-470, lcsh:Biotechnology, Longevity, 610 Medizin, GATK, Next-generation sequencing (NGS) technologies, Illumina, Complete genomics, Healthy aging, Wellderly, Platform-biases, Polymorphism, Single Nucleotide, 570 Life sciences, lcsh:TP248.13-248.65, 610 Medical sciences, 620 Engineering and allied operations, Humans, Computational Biology, High-Throughput Nucleotide Sequencing, Reproducibility of Results, Genomics, Physik (inkl. Astronomie), 620 Ingenieurwissenschaften und Maschinenbau, lcsh:Genetics, Cross-Sectional Studies, 570 Biowissenschaften, Research Article
Abstract: Background Next Generation Sequencing (NGS) is the fundament of various studies, providing insights into questions from biology and medicine. Nevertheless, integrating data from different experimental backgrounds can introduce strong biases. In order to methodically investigate the magnitude of systematic errors in single nucleotide variant calls, we performed a cross-sectional observational study on a genomic cohort of 99 subjects each sequenced via (i) Illumina HiSeq X, (ii) Illumina HiSeq, and (iii) Complete Genomics and processed with the respective bioinformatic pipeline. We also repeated variant calling for the Illumina cohorts with GATK, which allowed us to investigate the effect of the bioinformatics analysis strategy separately from the sequencing platform's impact.Results The number of detected variants/variant classes per individual was highly dependent on the experimental setup. We observed a statistically significant overrepresentation of variants uniquely called by a single setup, indicating potential systematic biases. Insertion/deletion polymorphisms (InDels) were associated with decreased concordance compared to single nucleotide polymorphisms (SNPs). The discrepancies in InDel absolute numbers were particularly prominent in introns, Alu elements, simple repeats, and regions with medium GC content. Notably, reprocessing sequencing data following the best practice recommendations of GATK considerably improved concordance between the respective setups.Conclusion We provide empirical evidence of systematic heterogeneity in variant calls between alternative experimental and data analysis setups. Furthermore, our results demonstrate the benefit of reprocessing genomic data with harmonized pipelines when integrating data from different studies.
Published: 2020

30. Inhibition of histone deacetylation rescues phenotype in a mouse model of Birk-Barel intellectual disability syndrome

Author: Susann Schweiger, Junaid Akhtar, Konstantin Radyushkin, Desiree Lucia Fend-Guella, Susanne Strand, Somanath Jagannath, Ulrich Zechner, Jennifer Winter, Florian Lesage, Jochen Roeper, Alexis Cooper, Niklas Hammer, Tamer Butto, Johannes Gutenberg - Universität Mainz (JGU), Goethe-University Frankfurt am Main, Laboratory of Excellence in Ion Channel Science and Therapeutics [Valbonne] (LabEx ICST), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Senckenberg Center of Human Genetics [Francfort, Allemagne], The work was supported by the Deutsche Forschungsgemeinschaft (CRC 1193 and CRC 1080). Alexis Cooper was funded by a fellowship of the Focus Program Translational Neurosciences Mainz., Bodescot, Myriam, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Male, 0301 basic medicine, Potassium Channels, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Physics and Astronomy, Disease, Phenylenediamines, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Craniofacial Abnormalities, Histones, Mice, 0302 clinical medicine, Intellectual disability, Imprinting (psychology), lcsh:Science, Mice, Knockout, Genetics, Multidisciplinary, Behavior, Animal, biology, Neurodevelopmental disorders, Developmental disorders, Brain, Phenotype, Up-Regulation, Histone, Gene Knockdown Techniques, Benzamides, Muscle Hypotonia, Female, Locus Coeruleus, Epigenetics, Science, Article, General Biochemistry, Genetics and Molecular Biology, Genomic Imprinting, 03 medical and health sciences, Intellectual Disability, medicine, Animals, Humans, ddc:610, Allele, Gene, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, medicine.disease, Histone Deacetylase Inhibitors, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Acetylation, Mutation, biology.protein, lcsh:Q, 030217 neurology & neurosurgery
Abstract: Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder., Birk-Barel intellectual disability is an imprinting syndrome due to maternally-only transmitted mutations of KCNK9/TASK3. Here authors are using a heterozygous deletion of the active maternal Kcnk9 allele to model the disease and show phenotypic rescue by HDAC inhibition.
Published: 2020

31. Point mutations in GLI3 lead to misregulation of its subcellular localization.

Author: Sybille Krauss, Joyce So, Melanie Hambrock, Andrea Köhler, Melanie Kunath, Constance Scharff, Martina Wessling, Karl-Heinz Grzeschik, Rainer Schneider, and Susann Schweiger
Subjects: Medicine, Science
Abstract: BACKGROUND:Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function. PRINCIPAL FINDINGS:We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-alpha4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity. CONCLUSIONS:The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations.
Published: 2009
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32. Active transport of the ubiquitin ligase MID1 along the microtubules is regulated by protein phosphatase 2A.

Author: Beatriz Aranda-Orgillés, Johanna Aigner, Melanie Kunath, Rudi Lurz, Rainer Schneider, and Susann Schweiger
Subjects: Medicine, Science
Abstract: Mutations in the MID1 protein have been found in patients with Opitz BBB/G syndrome (OS), which is characterised by multiple malformations of the ventral midline. MID1 is a microtubule-associated protein that stabilizes microtubules and, in association with the regulatory subunit of protein phosphatase 2A (PP2A), alpha4, provides ubiquitin ligase activity for the ubiquitin-specific modification of PP2A. Using Fluorescence Recovery After Photobleaching (FRAP) technology, we show here that MID1 is actively and bi-directionally transported along the microtubules, and that this movement is directly linked to its MAP kinase and PP2A-mediated phosphorylation status. Intact transport depends on both kinesins and dyneins and is inhibited upon colcemide treatments. MID1 proteins carrying missense mutations in the alpha4 binding domain still bind the microtubules but cannot be actively transported. Likewise, knock-down of the alpha4 protein, inhibition of PP2A activity by okadaic acid and fostriecin or the simulation of permanent phosphorylation at Ser96 in MID1 stop the migration of MID1-GFP, while preserving its microtubule-association. In summary, our data uncover an unexpected and novel function for PP2A, its regulatory subunit alpha4 and PP2A/alpha4/mTOR signaling in the active transport of the MID1 ubiquitin ligase complex along the cytoskeleton. Furthermore, a failure in the microtubule directed transport of this protein complex would be an attractive mechanism underlying the pathogenesis of OS in patients with B-box1 mutations.
Published: 2008
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33. Comparative 3'UTR analysis allows identification of regulatory clusters that drive Eph/ephrin expression in cancer cell lines.

Author: Jennifer Winter, Stefan Roepcke, Sven Krause, Eva-Christina Müller, Albrecht Otto, Martin Vingron, and Susann Schweiger
Subjects: Medicine, Science
Abstract: Eph receptors are the largest family of receptor tyrosine kinases. Together with their ligands, the ephrins, they fulfill multiple biological functions. Aberrant expression of Ephs/ephrins leading to increased Eph receptor to ephrin ligand ratios is a critical factor in tumorigenesis, indicating that tight regulation of Eph and ephrin expression is essential for normal cell behavior. The 3'-untranslated regions (3'UTRs) of transcripts play an important yet widely underappreciated role in the control of protein expression. Based on the assumption that paralogues of large gene families might exhibit a conserved organization of regulatory elements in their 3'UTRs we applied a novel bioinformatics/molecular biology approach to the 3'UTR sequences of Eph/ephrin transcripts. We identified clusters of motifs consisting of cytoplasmic polyadenylation elements (CPEs), AU-rich elements (AREs) and HuR binding sites. These clusters bind multiple RNA-stabilizing and destabilizing factors, including HuR. Surprisingly, despite its widely accepted role as an mRNA-stabilizing protein, we further show that binding of HuR to these clusters actually destabilizes Eph/ephrin transcripts in tumor cell lines. Consequently, knockdown of HuR greatly modulates expression of multiple Ephs/ephrins at both the mRNA and protein levels. Together our studies suggest that overexpression of HuR as found in many progressive tumors could be causative for disarranged Eph receptor to ephrin ligand ratios leading to a higher degree of tissue invasiveness.
Published: 2008
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34. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author: Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)
Subjects: 0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
Published: 2019

35. 18F-FDG PET/CT: an unexpected case of Huntington’s disease

Author: Hans-Georg Buchholz, Sebastian Michels, Oliver Tüscher, Mathias Schreckenberger, Susann Schweiger, Isabel Heinrich, Manuela A Hoffmann, and Florian Rosar
Subjects: Male, Pathology, medicine.medical_specialty, Neurology, Case Report, Disease, lcsh:RC346-429, 03 medical and health sciences, Striatal hypometabolism, 0302 clinical medicine, Huntington's disease, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography, medicine, Dementia, Humans, Neurochemistry, 030212 general & internal medicine, lcsh:Neurology. Diseases of the nervous system, business.industry, Brain, General Medicine, Middle Aged, medicine.disease, FDG-PET/CT, 3. Good health, Huntington Disease, Dyskinesia, Neurology (clinical), Neurosurgery, medicine.symptom, Differential diagnosis, business, 030217 neurology & neurosurgery, Huntington’s disease
Abstract: Background Huntington’s disease (HD) is a rare, genetic neurodegenerative disorder often presenting with emotional, cognitive and behavioral abnormalities before manifestation of disease defining motor symptoms. Cognitive impairment is a frequent clinical feature caused by different dementia subtypes. Imaging cortical and subcortical glucose metabolism via 18F-FDG PET/CT can help to discriminate the underlying disease. Case presentation The patient is a 54-year old man presenting with progressive cognitive impairment and mild orofacial dyskinesia. 18F-FDG PET/CT of the brain revealed a severe bilateral hypometabolism in the striatum. Following imaging Huntington’s disease was suspected and a molecular genetic testing confirmed the diagnosis. Conclusions Huntington’s disease is a rare but important differential diagnosis of cognitive impairment, especially before motor symptoms are manifest. 18F-FDG PET is capable to show early striatal dysfunction in HD even when structural imaging is normal. We conclude that, in cases with negative family history the HD characteristic metabolic pattern can lead to the diagnosis when no other dementia-suspected changes are present.
Published: 2019

36. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author: Kathleen M. Gorman, Esther Meyer, Detelina Grozeva, Egidio Spinelli, Amy McTague, Alba Sanchis-Juan, Keren J. Carss, Emily Bryant, Adi Reich, Amy L. Schneider, Ronit M. Pressler, Michael A. Simpson, Geoff D. Debelle, Evangeline Wassmer, Jenny Morton, Diana Sieciechowicz, Eric Jan-Kamsteeg, Alex R. Paciorkowski, Mary D. King, J. Helen Cross, Annapurna Poduri, Heather C. Mefford, Ingrid E. Scheffer, Tobias B. Haack, Gary McCullagh, John J. Millichap, Gemma L. Carvill, Jill Clayton-Smith, Eamonn R. Maher, F. Lucy Raymond, Manju A. Kurian, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Siddharth Banka, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Saeed Al Turki, Carl Anderson, Richard Anney, Dinu Antony, Maria Soler Artigas, Muhammad Ayub, Senduran Balasubramaniam, Inês Barroso, Phil Beales, Jamie Bentham, Shoumo Bhattacharya, Ewan Birney, Douglas Blackwood, Martin Bobrow, Elena Bochukova, Patrick Bolton, Rebecca Bounds, Chris Boustred, Gerome Breen, Mattia Calissano, Keren Carss, Krishna Chatterjee, Lu Chen, Antonio Ciampi, Sebhattin Cirak, Peter Clapham, Gail Clement, Guy Coates, David Collier, Catherine Cosgrove, Tony Cox, Nick Craddock, Lucy Crooks, Sarah Curran, David Curtis, Allan Daly, Aaron Day-Williams, Ian N.M. Day, Thomas Down, Yuanping Du, Ian Dunham, Sarah Edkins, Peter Ellis, David Evans, Sadaf Faroogi, Ghazaleh Fatemifar, David R. Fitzpatrick, Paul Flicek, James Flyod, A. Reghan Foley, Christopher S. Franklin, Marta Futema, Louise Gallagher, Matthias Geihs, Daniel Geschwind, Heather Griffin, Xueqin Guo, Xiaosen Guo, Hugh Gurling, Deborah Hart, Audrey Hendricks, Peter Holmans, Bryan Howie, Liren Huang, Tim Hubbard, Steve E. Humphries, Pirro Hysi, David K. Jackson, Yalda Jamshidi, Tian Jing, Chris Joyce, Jane Kaye, Thomas Keane, Julia Keogh, John Kemp, Karen Kennedy, Anja Kolb-Kokocinski, Genevieve Lachance, Cordelia Langford, Daniel Lawson, Irene Lee, Monkol Lek, Jieqin Liang, Hong Lin, Rui Li, Yingrui Li, Ryan Liu, Jouko Lönnqvist, Margarida Lopes, Valentina Iotchkova, Daniel MacArthur, Jonathan Marchini, John Maslen, Mangino Massimo, Iain Mathieson, Gaëlle Marenne, Peter McGuffin, Andrew McIntosh, Andrew G. McKechanie, Andrew McQuillin, Sarah Metrustry, Hannah Mitchison, Alireza Moayyeri, James Morris, Francesco Muntoni, Kate Northstone, Michael O'Donnovan, Alexandros Onoufriadis, Stephen O'Rahilly, Karim Oualkacha, Michael J. Owen, Aarno Palotie, Kalliope Panoutsopoulou, Victoria Parker, Jeremy R. Parr, Lavinia Paternoster, Tiina Paunio, Felicity Payne, Olli Pietilainen, Vincent Plagnol, Lydia Quaye, Michael A. Quail, Karola Rehnström, Susan Ring, Graham R.S. Ritchie, Nicola Roberts, David B. Savage, Peter Scambler, Stephen Schiffels, Miriam Schmidts, Nadia Schoenmakers, Robert K. Semple, Eva Serra, Sally I. Sharp, So-Youn Shin, David Skuse, Kerrin Small, Lorraine Southam, Olivera Spasic-Boskovic, David St Clair, Jim Stalker, Elizabeth Stevens, Beate St Pourcian, Jianping Sun, Jaana Suvisaari, Ionna Tachmazidou, Martin D. Tobin, Ana Valdes, Margriet Van Kogelenberg, Peter M. Visscher, Louise V. Wain, James T.R. Walters, Guangbiao Wang, Jun Wang, Yu Wang, Kirsten Ward, Elanor Wheeler, Tamieka Whyte, Hywel Williams, Kathleen A. Williamson, Crispian Wilson, Kim Wong, ChangJiang Xu, Jian Yang, Fend Zhang, Pingbo Zhang, Timothy Aitman, Hana Alachkar, Sonia Ali, Louise Allen, David Allsup, Gautum Ambegaonkar, Julie Anderson, Richard Antrobus, Gavin Arno, Gururaj Arumugakani, Sofie Ashford, William Astle, Antony Attwood, Steve Austin, Chiara Bacchelli, Tamam Bakchoul, Tadbir K. Bariana, Helen Baxendale, David Bennett, Claire Bethune, Shahnaz Bibi, Marta Bleda, Harm Boggard, Paula Bolton-Maggs, Claire Booth, John R. Bradley, Angie Brady, Matthew Brown, Michael Browning, Christine Bryson, Siobhan Burns, Paul Calleja, Jenny Carmichael, Mark Caulfield, Elizabeth Chalmers, Anita Chandra, Patrick Chinnery, Manali Chitre, Colin Church, Emma Clement, Naomi Clements-Brod, Gerry Coghlan, Peter Collins, Nichola Cooper, Amanda Creaser-Myers, Rosa DaCosta, Louise Daugherty, Sophie Davies, John Davis, Minka De Vries, Patrick Deegan, Sri V.V. Deevi, Lisa Devlin, Eleanor Dewhurst, Rainer Doffinger, Natalie Dormand, Elizabeth Drewe, David Edgar, William Egner, Wendy N. Erber, Marie Erwood, Tamara Everington, Remi Favier, Helen Firth, Debra Fletcher, James C. Fox, Amy Frary, Kathleen Freson, Bruce Furie, Abigail Furnell, Daniel Gale, Alice Gardham, Michael Gattens, Pavandeep K. Ghataorhe, Rohit Ghurye, Simon Gibbs, Kimberley Gilmour, Paul Gissen, Sarah Goddard, Keith Gomez, Pavel Gordins, Stefan Gräf, Daniel Greene, Alan Greenhalgh, Andreas Greinacher, Sofia Grigoriadou, Scott Hackett, Charaka Hadinnapola, Rosie Hague, Matthias Haimel, Csaba Halmagyi, Tracey Hammerton, Daniel Hart, Grant Hayman, Johan W.M. Heemskerk, Robert Henderson, Anke Hensiek, Yvonne Henskens, Archana Herwadkar, Fengyuan Hu, Aarnoud Huissoon, Marc Humbert, Roger James, Stephen Jolles, Rashid Kazmi, David Keeling, Peter Kelleher, Anne M. Kelly, Fiona Kennedy, David Kiely, Nathalie Kingston, Ania Koziell, Deepa Krishnakumar, Taco W. Kuijpers, Dinakantha Kumararatne, Manju Kurian, Michael A. Laffan, Michele P. Lambert, Hana Lango Allen, Allan Lawrie, Sara Lear, Claire Lentaigne, Ri Liesner, Rachel Linger, Hilary Longhurst, Lorena Lorenzo, Rajiv Machado, Rob Mackenzie, Robert MacLaren, Eamonn Maher, Jesmeen Maimaris, Sarah Mangles, Ania Manson, Rutendo Mapeta, Hugh S. Markus, Jennifer Martin, Larahmie Masati, Mary Mathias, Vera Matser, Anna Maw, Elizabeth McDermott, Coleen McJannet, Stuart Meacham, Sharon Meehan, Karyn Megy, Michel Michaelides, Carolyn M. Millar, Shahin Moledina, Anthony Moore, Nicholas Morrell, Andrew Mumford, Sai Murng, Elaine Murphy, Sergey Nejentsev, Sadia Noorani, Paquita Nurden, Eric Oksenhendler, Willem H. Ouwehand, Sofia Papadia, Alasdair Parker, John Pasi, Chris Patch, Jeanette Payne, Andrew Peacock, Kathelijne Peerlinck, Christopher J. Penkett, Joanna Pepke-Zaba, David J. Perry, Val Pollock, Gary Polwarth, Mark Ponsford, Waseem Qasim, Isabella Quinti, Stuart Rankin, Karola Rehnstrom, Evan Reid, Christopher J. Rhodes, Michael Richards, Sylvia Richardson, Alex Richter, Irene Roberts, Matthew Rondina, Catherine Roughley, Kevin Rue-Albrecht, Crina Samarghitean, Saikat Santra, Ravishankar Sargur, Sinisa Savic, Sol Schulman, Harald Schulze, Marie Scully, Suranjith Seneviratne, Carrock Sewell, Olga Shamardina, Debbie Shipley, Ilenia Simeoni, Suthesh Sivapalaratnam, Kenneth Smith, Aman Sohal, Laura Southgate, Simon Staines, Emily Staples, Hans Stauss, Penelope Stein, Jonathan Stephens, Kathleen Stirrups, Sophie Stock, Jay Suntharalingam, R. Campbell Tait, Kate Talks, Yvonne Tan, Jecko Thachil, James Thaventhiran, Ellen Thomas, Moira Thomas, Dorothy Thompson, Adrian Thrasher, Catherine Titterton, Cheng-Hock Toh, Mark Toshner, Carmen Treacy, Richard Trembath, Salih Tuna, Wojciech Turek, Ernest Turro, Chris Van Geet, Marijke Veltman, Julie von Ziegenweldt, Anton Vonk Noordegraaf, Ivy Wanjiku, Timothy Q. Warner, Hugh Watkins, Andrew Webster, Steve Welch, Sarah Westbury, John Wharton, Deborah Whitehorn, Martin Wilkins, Lisa Willcocks, Catherine Williamson, Geoffrey Woods, John Wort, Nigel Yeatman, Patrick Yong, Tim Young, Ping Yu, Paediatric Infectious Diseases / Rheumatology / Immunology, ARD - Amsterdam Reproduction and Development, Pediatric surgery, APH - Aging & Later Life, Molecular cell biology and Immunology, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Adolescent, Loss of Heterozygosity, Context (language use), Postnatal microcephaly, Neurotransmission, medicine.disease_cause, Bioinformatics, Synaptic Transmission, Loss of heterozygosity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Calcium Channels, N-Type, Report, Genetics, medicine, Humans, Child, Genetics (clinical), Mutation, Dyskinesias, business.industry, Infant, medicine.disease, Hypotonia, Pedigree, 030104 developmental biology, Dyskinesia, Child, Preschool, Calcium, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: © 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.
Published: 2018

37. CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

Author: Ulrich Zechner, Eva Weis, Anna Etzold, Susann Schweiger, Thomas Haaf, Dennis Strand, Timo Itzel, Oliver Bartsch, Claudia Spix, Susanne Strand, and Danuta Galetzka
Subjects: Adult, 0301 basic medicine, Cancer Research, Twins, Haploinsufficiency, Ketone Bodies, Extracellular matrix, Transcriptome, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, Genes, Tumor Suppressor, Molecular Biology, PDPN, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Skin, Extracellular Matrix Proteins, biology, BRCA1 Protein, Cell growth, Genes, Homeobox, Cancer, DNA Methylation, Fibroblasts, medicine.disease, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Culture Media, Conditioned, Mutation, DNA methylation, Immunology, Cancer research, biology.protein, Cytokines, Cancer-Associated Fibroblasts, Female, Neoplasm Recurrence, Local, ACTA2, Research Paper
Abstract: Constitutive epimutations of tumor suppressor genes are increasingly considered as cancer predisposing factors equally to sequence mutations. In light of the emerging role of the microenvironment for cancer predisposition, initiation, and progression, we aimed to characterize the consequences of a BRCA1 epimutation in cells of mesenchymal origin. We performed a comprehensive molecular and cellular comparison of primary dermal fibroblasts taken from a monozygous twin pair discordant for recurrent cancers and BRCA1 epimutation, whose exceptional clinical case we previously reported in this journal. Comparative transcriptome analysis identified differential expression of extracellular matrix-related genes and pro-tumorigenic growth factors, such as collagens and CXC chemokines. Moreover, genes known to be key markers of so called cancer-associated fibroblasts (CAFs), such as ACTA2, FAP, PDPN, and TNC, were upregulated in fibroblasts of the affected twin (BRCA1mosMe) in comparison to those of the healthy twin (BRCA1wt). Further analyses detected CAF-typical cellular features, including an elevated growth rate, enhanced migration, altered actin architecture and increased production of ketone bodies in BRCA1mosMe fibroblasts compared to BRCA1wt fibroblasts. In addition, conditioned medium of BRCA1mosMe fibroblasts was more potent than conditioned medium of BRCA1wt fibroblasts to promote cell proliferation in an epithelial and a cancer cell line. Our data demonstrate, that a CAF-like state is not an exclusive feature of tumor-associated tissue but also exists in healthy tissue with tumor suppressor deficiency. The naturally occurring phenomenon of twin fibroblasts differing in their BRCA1 methylation status revealed to be a unique powerful tool for exploring tumor suppressor deficiency-related changes in healthy tissue, reinforcing their significance for cancer predisposition.
Published: 2016

38. Morbus Huntington: Diagnostik und aktuelle Entwicklungen

Author: Oliver Tüscher and Susann Schweiger
Subjects: General Medicine
Published: 2015

39. Author response: Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease

Author: Hirofumi Watari, Sybille Krauss, Katharina Meyer, Sven Buettner, Isabelle Arnoux, Axel Methner, Rosamund F. Langston, Nina Offermann, Daniele Bano, Konstantin Radyushkin, Jennifer Krummeich, Partha Narayan Dey, Erich E. Wanker, Jeremy J. Lambert, Stephanie Weber, Susann Schweiger, Olivia Monteiro, Nadine Griesche, Changwei Chen, Albrecht Stroh, and Michael Willam
Subjects: Huntington's disease, business.industry, Cortical network, Behavior change, Medicine, business, medicine.disease, Neuroscience, Metformin, medicine.drug
Published: 2018

40. Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease

Author: Jennifer Krummeich, Jeremy J. Lambert, Axel Methner, Sven Buettner, Isabelle Arnoux, Hirofumi Watari, Nina Offermann, Daniele Bano, Sybille Krauss, Michael Willam, Albrecht Stroh, Konstantin Radyushkin, Erich E. Wanker, Susann Schweiger, Olivia Monteiro, Stephanie Weber, Rosamund F. Langston, Partha Narayan Dey, Nadine Griesche, Changwei Chen, and Katharina Meyer
Subjects: physiopathology [Huntington Disease], 0301 basic medicine, Clinical manifestation, Disease, drug effects [Cerebral Cortex], physiopathology [Cerebral Cortex], drug effects [Behavior, Animal], physiopathology [Nerve Net], metabolism [Calcium], Biology (General), Cerebral Cortex, Neurons, Huntingtin Protein, metabolism [Astrocytes], Behavior, Animal, General Neuroscience, Behavior change, drug effects [Mitochondria], in vivo calcium imaging, General Medicine, drug effects [Caenorhabditis elegans], Metformin, Mitochondria, medicine.anatomical_structure, Huntington Disease, pathology [Huntington Disease], metabolism [Neurons], Cortical network, Medicine, Function and Dysfunction of the Nervous System, medicine.drug, QH301-705.5, neuronal hyperactivity, Science, Cell Respiration, drug effects [Astrocytes], Time-Lapse Imaging, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Protein Aggregates, Huntington's disease, drug effects [Nerve Net], medicine, drug effects [Cell Respiration], drug effects [Neurons], Animals, metabolism [Mutant Proteins], Caenorhabditis elegans, Photons, cortical microcircuits, General Immunology and Microbiology, business.industry, drug effects [Protein Aggregates], metabolism [Mitochondria], medicine.disease, Disease Models, Animal, Kinetics, 030104 developmental biology, Visual cortex, Astrocytes, Protein Biosynthesis, metabolism [Huntingtin Protein], Calcium, Mutant Proteins, pharmacology [Metformin], Nerve Net, business, ddc:600, Neuroscience
Abstract: Catching primal functional changes in early, ‘very far from disease onset’ (VFDO) stages of Huntington’s disease is likely to be the key to a successful therapy. Focusing on VFDO stages, we assessed neuronal microcircuits in premanifest Hdh150 knock-in mice. Employing in vivo two-photon Ca2+ imaging, we revealed an early pattern of circuit dysregulation in the visual cortex - one of the first regions affected in premanifest Huntington’s disease - characterized by an increase in activity, an enhanced synchronicity and hyperactive neurons. These findings are accompanied by aberrations in animal behavior. We furthermore show that the antidiabetic drug metformin diminishes aberrant Huntingtin protein load and fully restores both early network activity patterns and behavioral aberrations. This network-centered approach reveals a critical window of vulnerability far before clinical manifestation and establishes metformin as a promising candidate for a chronic therapy starting early in premanifest Huntington’s disease pathogenesis long before the onset of clinical symptoms.
Published: 2018

41. Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

Author: Susann Schweiger, Peter Meyer, Michael Beck, Katalin Komlosi, Desiree Lucia Fend-Guella, Ulrich Zechner, Jennifer Winter, Stefan Diederich, and Oliver Bartsch
Subjects: panel diagnostics, Male, 0301 basic medicine, Candidate gene, Genetic counseling, lcsh:Medicine, carrier screening, Genes, Recessive, 030105 genetics & heredity, Carrier testing, Preimplantation genetic diagnosis, DNA sequencing, 03 medical and health sciences, Humans, Medicine, Pharmacology (medical), Gene, Genetics (clinical), next generation sequencing, Genetics, business.industry, Research, lcsh:R, High-Throughput Nucleotide Sequencing, autosomal recessive, General Medicine, Microarray Analysis, Phenotype, Human genetics, Pedigree, consanguineous, Female, business
Abstract: Background Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. Methods We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. Results The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. Conclusions For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions. Electronic supplementary material The online version of this article (10.1186/s13023-018-0763-0) contains supplementary material, which is available to authorized users.
Published: 2018

42. Pharmacological disruption of the MID1/α4 interaction reduces mutant Huntingtin levels in primary neuronal cultures

Author: Rachel Buxton, Jeremy J. Lambert, Angela Bridges, Rosamund F. Langston, Argyrides Argyrou, Emma J. Jones, Christina Pancevac Jönsson, Susann Schweiger, Olivia Monteiro, Kelly M Gatfield, Changwei Chen, Ryan P. Bingham, Sybille Krauß, and Iain Uings
Subjects: 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Huntingtin, Mid1 protein, mouse, Protein subunit, Ubiquitin-Protein Ligases, Mutant, Primary Cell Culture, Peptide, 03 medical and health sciences, Mice, Huntington's disease, mental disorders, medicine, Animals, Humans, Htt protein, mouse, ddc:610, Protein Phosphatase 2, Neurons, chemistry.chemical_classification, Messenger RNA, Huntingtin Protein, biology, Chemistry, General Neuroscience, Proteins, genetics [Huntingtin Protein], metabolism [Protein Phosphatase 2], metabolism [Proteins], Protein phosphatase 2, medicine.disease, Ubiquitin ligase, Cell biology, 030104 developmental biology, HEK293 Cells, metabolism [Neurons], metabolism [Huntingtin Protein], Mutation, biology.protein, Protein Binding
Abstract: Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from HdhQ111/Q7 mice. This data serves to validate this pathway and paves the way for the discovery of small molecule inhibitors of this interaction as potential therapies for HD.
Published: 2018

43. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author: Víctor Faundes, William G. Newman, Laura Bernardini, Natalie Canham, Jill Clayton-Smith, Bruno Dallapiccola, Sally J. Davies, Michelle K. Demos, Amy Goldman, Harinder Gill, Rachel Horton, Bronwyn Kerr, Dhavendra Kumar, Anna Lehman, Shane McKee, Jenny Morton, Michael J. Parker, Julia Rankin, Lisa Robertson, I. Karen Temple, Siddharth Banka, Shelin Adam, Christèle du Souich, Alison M. Elliott, Jill Mwenifumbo, Tanya N. Nelson, Clara van Karnebeek, Jan M. Friedman, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Helen Cox, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, V.K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Julie Vogt, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, and Matthew E. . Hurles
Subjects: 0301 basic medicine, ASH1L, Male, Methyltransferase, Adolescent, Histone lysine methylation, KMT5B, Developmental Disabilities, Haploinsufficiency, Biology, Compound heterozygosity, histone lysine methyltransferase, Chromatin remodeling, chromatin remodeling, 03 medical and health sciences, histone lysine demethylase, Report, Genetics, Humans, Child, Genetics (clinical), Regulation of gene expression, Histone Demethylases, Developmental disorders, KMT2C, KMT2B, Histone-Lysine N-Methyltransferase, 030104 developmental biology, Histone, Overgrowth syndrome, Child, Preschool, Mutation, biology.protein, KDM5B, Female
Abstract: Histone lysine methyltransferases (KMTs) and demethylases (KDMs) underpin gene regulation. Here we demonstrate that variants causing haploinsufficiency of KMTs and KDMs are frequently encountered in individuals with developmental disorders. Using a combination of human variation databases and existing animal models, we determine 22 KMTs and KDMs as additional candidates for dominantly inherited developmental disorders. We show that KMTs and KDMs that are associated with, or are candidates for, dominant developmental disorders tend to have a higher level of transcription, longer canonical transcripts, more interactors, and a higher number and more types of post-translational modifications than other KMT and KDMs. We provide evidence to firmly associate KMT2C, ASH1L, and KMT5B haploinsufficiency with dominant developmental disorders. Whereas KMT2C or ASH1L haploinsufficiency results in a predominantly neurodevelopmental phenotype with occasional physical anomalies, KMT5B mutations cause an overgrowth syndrome with intellectual disability. We further expand the phenotypic spectrum of KMT2B-related disorders and show that some individuals can have severe developmental delay without dystonia at least until mid-childhood. Additionally, we describe a recessive histone lysine-methylation defect caused by homozygous or compound heterozygous KDM5B variants and resulting in a recognizable syndrome with developmental delay, facial dysmorphism, and camptodactyly. Collectively, these results emphasize the significance of histone lysine methylation in normal human development and the importance of this process in human developmental disorders. Our results demonstrate that systematic clinically oriented pathway-based analysis of genomic data can accelerate the discovery of rare genetic disorders.
Published: 2017

44. The E3 Ubiquitin Ligase MID1 Catalyzes Ubiquitination and Cleavage of Fu

Author: Sybille Krauß, Eva-Christina Müller, Frank Matthes, Melanie Fuchs, Andrea Köhler, Stephanie Dorn, Rainer Schneider, Susann Schweiger, and Erich E. Wanker
Subjects: metabolism [Microtubule Proteins], Ubiquitin-conjugating enzyme, Biochemistry, metabolism [Protein Serine-Threonine Kinases], Ubiquitin, metabolism [Transcription Factors], Nuclear protein, Sonic hedgehog, biology, metabolism [Protein-Serine-Threonine Kinases], Nuclear Proteins, respiratory system, Protein-Serine-Threonine Kinases, Ubiquitin ligase, Gene Expression Regulation, Neoplastic, GLI3 protein, human, ddc:540, embryonic structures, Microtubule Proteins, metabolism [Hedgehog Proteins], Function and Dysfunction of the Nervous System, metabolism [Nuclear Proteins], Signal Transduction, metabolism [Kruppel-Like Transcription Factors], Proteasome Endopeptidase Complex, animal structures, STK36 protein, human, Ubiquitin-Protein Ligases, Kruppel-Like Transcription Factors, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, chemistry [Ubiquitin-Protein Ligases], Catalysis, Zinc Finger Protein Gli3, Cell Line, Tumor, GLI3, Humans, Hedgehog Proteins, metabolism [Proteasome Endopeptidase Complex], metabolism [Cell Nucleus], Molecular Biology, chemistry [Lysine], DNA Primers, Cell Nucleus, metabolism [Nerve Tissue Proteins], Lysine, Ubiquitination, Cell Biology, Protein phosphatase 2, chemistry [Ubiquitin], Proteasome, biology.protein, SHH protein, human, human activities, Mid1 protein, human, HeLa Cells, Transcription Factors
Abstract: Sonic Hedgehog (SHH)-GLI signalling plays an important role during embryogenesis and in tumorigenesis. The survival and growth of several types of cancer depend on autonomously activated SHH-GLI signalling. A protein complex containing the ubiquitin-ligase MID1 and protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity of GLI3, a transcriptional effector molecule of SHH, in cancer cell lines with autonomously activated SHH signalling. However, the exact molecular mechanisms that mediate the interaction between MID1 and GLI3 remained unknown. Here, we show that MID1 catalyses the ubiquitination and proteasomal cleavage of the GLI3-regulator Fu. Our data suggest that Fu ubiquitination and cleavage is one of the key elements connecting the MID1/PP2A protein complex with GLI3 activity control.
Published: 2014

45. Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex

Author: Sybille Krauß, Karen L. Posey, Stephanie Weber, Susann Schweiger, Frank Matthes, Rainer Schneider, Dan Ehninger, Sandra Pfurtscheller, Eva Kickstein, and Moritz M. Hettich
Subjects: 0301 basic medicine, metabolism [Microtubule Proteins], lcsh:Medicine, Resveratrol, Microtubules, pathology [Alzheimer Disease], Mice, chemistry.chemical_compound, 0302 clinical medicine, antagonists & inhibitors [Protein Phosphatase 2], drug therapy [Alzheimer Disease], pathology [Neurons], metabolism [Transcription Factors], Protein Interaction Maps, Protein Phosphatase 2, Phosphorylation, lcsh:Science, Cells, Cultured, Neurons, Multidisciplinary, biology, Chemistry, Anti-Inflammatory Agents, Non-Steroidal, Nuclear Proteins, Neurofibrillary Tangles, metabolism [Proteins], Ubiquitin ligase, Cell biology, drug effects [Microtubules], metabolism [Neurons], Microtubule Proteins, pathology [Fibroblasts], metabolism [Alzheimer Disease], metabolism [Fibroblasts], metabolism [Nuclear Proteins], antagonists & inhibitors [Microtubule Proteins], drug effects [Embryo, Mammalian], Mid1 protein, mouse, pathology [Embryo, Mammalian], metabolism [Microtubules], Ubiquitin-Protein Ligases, Protein subunit, Tau protein, Phosphatase, tau Proteins, Article, Dephosphorylation, pharmacology [Anti-Inflammatory Agents, Non-Steroidal], antagonists & inhibitors [Transcription Factors], 03 medical and health sciences, antagonists & inhibitors [Proteins], Alzheimer Disease, Animals, Humans, drug effects [Neurons], metabolism [Embryo, Mammalian], drug effects [Fibroblasts], lcsh:R, Proteins, metabolism [Protein Phosphatase 2], Protein phosphatase 2, Fibroblasts, Embryo, Mammalian, pharmacology [Resveratrol], metabolism [tau Proteins], HEK293 Cells, 030104 developmental biology, Proteolysis, antagonists & inhibitors [Nuclear Proteins], biology.protein, drug effects [Protein Interaction Maps], lcsh:Q, ddc:600, 030217 neurology & neurosurgery, Transcription Factors, Mid1 protein, human
Abstract: The formation of paired helical filaments (PHF), which are composed of hyperphosphorylated Tau protein dissociating from microtubules, is one of the pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. The most important phosphatase that is capable of dephosphorylating Tau at AD specific phospho-sites is protein phosphatase 2 A (PP2A). Here we show that resveratrol, a polyphenol, significantly induces PP2A activity and reduces Tau phosphorylation at PP2A-dependent epitopes. The increase in PP2A activity is caused by decreased expression of the MID1 ubiquitin ligase that mediates ubiquitin-specific modification and degradation of the catalytic subunit of PP2A when bound to microtubules. Interestingly, we further show that MID1 expression is elevated in AD tissue. Our data suggest a key role of MID1 in the pathology of AD and related tauopathies. Together with previous studies showing that resveratrol reduces β-amyloid toxicity they also give evidence of a promising role for resveratrol in the prophylaxis and therapy of AD.
Published: 2017

46. Mitochondrial function and energy metabolism in neuronal HT22 cells resistant to oxidative stress

Author: Annika Pfeiffer, Martin Jaeckel, Rebecca Noack, Jennifer Winter, Teresa Schacht, Jan Lewerenz, Christina Hoffmann, Axel Methner, Michael K. E. Schäfer, Alireza Pouya, and Susann Schweiger
Subjects: Pharmacology, Oligomycin, ATP synthase, Cellular respiration, Oxidative phosphorylation, Mitochondrion, Biology, medicine.disease_cause, chemistry.chemical_compound, Mitochondrial permeability transition pore, Biochemistry, chemistry, medicine, biology.protein, ATP–ADP translocase, Oxidative stress
Abstract: Background and Purpose The hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Extracellular glutamate depletes cellular glutathione by blocking the glutamate/cystine antiporter system xc−. Glutathione depletion induces a well-defined programme of cell death characterized by an increase in reactive oxygen species and mitochondrial dysfunction. Experimental Approach We compared the mitochondrial shape, the abundance of mitochondrial complexes and the mitochondrial respiration of HT22 cells, selected based on their resistance to glutamate, with those of the glutamate-sensitive parental cell line. Key Results Glutamate-resistant mitochondria were less fragmented and displayed seemingly contradictory features: mitochondrial calcium and superoxide were increased while high-resolution respirometry suggested a reduction in mitochondrial respiration. This was interpreted as a reverse activity of the ATP synthase under oxidative stress, leading to hydrolysis of ATP to maintain or even elevate the mitochondrial membrane potential, suggesting these cells endure ineffective energy metabolism to protect their membrane potential. Glutamate-resistant cells were also resistant to oligomycin, an inhibitor of the ATP synthase, but sensitive to deoxyglucose, an inhibitor of hexokinases. Exchanging glucose with galactose rendered resistant cells 1000-fold more sensitive to oligomycin. These results, together with a strong increase in cytosolic hexokinase 1 and 2, a reduced lactate production and an increased activity of glucose-6-phosphate dehydrogenase, suggest that glutamate-resistant HT22 cells shuttle most available glucose towards the hexose monophosphate shunt to increase glutathione recovery. Conclusions and Implications These results indicate that mitochondrial and metabolic adaptations play an important role in the resistance of cells to oxidative stress. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8
Published: 2014

47. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author: Sixto García-Miñaur, Ratna Veeramachaneni, Susan Price, Nicola Ragge, Kay Metcalfe, Graeme C.M. Black, Christopher P. Bennett, William Reardon, Alex Magee, Soo Mi Park, Jill Clayton-Smith, Nicole Revencu, Bruce Castle, Christine Oley, Wayne W.K. Lam, Vivienne McConnell, Deirdre E. Donnelly, Deepthi De Silva, Andrew E. Fry, I. Karen Temple, Judith A. Goodship, Helen Kingston, Gunnar Houge, Fiona Stewart, Sally J. Davies, Frances Elmslie, John Tolmie, Sancha Bunstone, Harinder Gill, Emma Howard, Shehla Mohammed, Moira Blyth, Michael Parker, Emma Hobson, Dian Donnai, Michael Wright, Kate Chandler, Amanda L. Collins, Susann Schweiger, Katherine Lachlan, Alex Henderson, Richard Gibbons, Siren Berland, Audrey Smith, Sally Ann Lynch, Pradeep Vasudevan, Bronwyn Kerr, Richard Fisher, Meriel McEntagart, Jenny Morton, Siddharth Banka, Yanick J. Crow, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Centre de génétique médicale UCL
Subjects: Biology, medicine.disease_cause, Article, Cohort Studies, Genetic Heterogeneity, Exon, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, Epigenetics, Genetics (clinical), Mutation, Genetic heterogeneity, Cancer, Sequence Analysis, DNA, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Face, Female, Kabuki syndrome
Abstract: MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. © 2012 Macmillan Publishers Limited All rights reserved.
Published: 2011

48. Protein Phosphatase 2A (PP2A)-specific Ubiquitin Ligase MID1 Is a Sequence-dependent Regulator of Translation Efficiency Controlling 3-Phosphoinositide-dependent Protein Kinase-1 (PDPK-1)

Author: Andrea Köhler, Désirée Rutschow, Susann Schweiger, Stefan Roepcke, Antonios I. Karagiannidis, Raphael Zeller, David M.J. Lilley, Sven Krause, Timothy J. Wilson, Rainer Schneider, Changwei Chen, and Beatriz Aranda-Orgillés
Subjects: Ubiquitin-Protein Ligases, macromolecular substances, Protein Serine-Threonine Kinases, environment and public health, Biochemistry, 3-Phosphoinositide-Dependent Protein Kinases, DDB1, Esophagus, HSPA2, Humans, RNA, Messenger, Molecular Biology, Hypospadias, Hypertelorism, biology, GRB10, Nuclear Proteins, RNA-Binding Proteins, Molecular Bases of Disease, Cell Biology, Protein phosphatase 2, Autophagy-related protein 13, Ubiquitin ligase, GPS2, enzymes and coenzymes (carbohydrates), EIF4EBP1, Protein Biosynthesis, embryonic structures, Microtubule Proteins, biology.protein, HeLa Cells, Transcription Factors
Abstract: We have shown previously that the ubiquitin ligase MID1, mutations of which cause the midline malformation Opitz BBB/G syndrome (OS), serves as scaffold for a microtubule-associated protein complex that regulates protein phosphatase 2A (PP2A) activity in a ubiquitin-dependent manner. Here, we show that the MID1 protein complex associates with mRNAs via a purine-rich sequence motif called MIDAS (MID1 association sequence) and thereby increases stability and translational efficiency of these mRNAs. Strikingly, inclusion of multiple copies of the MIDAS motif into mammalian mRNAs increases production of the encoded proteins up to 20-fold. Mutated MID1, as found in OS patients, loses its influence on MIDAS-containing mRNAs, suggesting that the malformations in OS patients could be caused by failures in the regulation of cytoskeleton-bound protein translation. This is supported by the observation that the majority of mRNAs that carry MIDAS motifs is involved in developmental processes and/or energy homeostasis. Further analysis of one of the proteins encoded by a MIDAS-containing mRNA, namely PDPK-1 (3-phosphoinositide dependent protein kinase-1), which is an important regulator of mammalian target of rapamycin/PP2A signaling, showed that PDPK-1 protein synthesis is significantly reduced in cells from an OS patient compared with an age-matched control and can be rescued by functional MID1. Together, our data uncover a novel messenger ribonucleoprotein complex that regulates microtubule-associated protein translation. They suggest a novel mechanism underlying OS and point at an enormous potential of the MIDAS motif to increase the efficiency of biotechnological protein production in mammalian cells.
Published: 2011

49. Protein Phosphatase 2A and Rapamycin Regulate the Nuclear Localization and Activity of the Transcription Factor GLI3

Author: Susann Schweiger, Sybille Krauß, Rainer Schneider, and John Foerster
Subjects: Cancer Research, Transcription, Genetic, Fluorescent Antibody Technique, mTORC1, Receptors, G-Protein-Coupled, Cytosol, Neoplasms, Tumor Cells, Cultured, Protein Phosphatase 2, Sonic hedgehog, biology, Reverse Transcriptase Polymerase Chain Reaction, TOR Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Cell biology, Protein Transport, Oncology, embryonic structures, Immunosuppressive Agents, Signal Transduction, Subcellular Fractions, animal structures, Green Fluorescent Proteins, Kruppel-Like Transcription Factors, Nerve Tissue Proteins, Mechanistic Target of Rapamycin Complex 1, Zinc Finger Protein Gli2, Zinc Finger Protein GLI1, Cyclin D1, Zinc Finger Protein Gli3, GLI1, Cyclin D, Cyclins, GLI2, GLI3, Humans, Hedgehog Proteins, RNA, Messenger, Transcription factor, Adaptor Proteins, Signal Transducing, Cell Nucleus, Sirolimus, Proteins, Protein phosphatase 2, Multiprotein Complexes, biology.protein, Cancer research, Molecular Chaperones, Transcription Factors
Abstract: Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, α4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin. [Cancer Res 2008;68(12):4658–65]
Published: 2008

50. The Opitz syndrome gene product MID1 assembles a microtubule-associated ribonucleoprotein complex

Author: Rainer Schneider, Alexander Trockenbacher, Johanna Aigner, Jennifer Winter, Ewa Jastrzebska, Beatriz Aranda-Orgillés, Albrecht Otto, Eva-Christina Müller, Erich E. Wanker, Andrea Köhler, Susann Schweiger, and Joachim Stahl
Subjects: Ubiquitin-Protein Ligases, Protein subunit, Molecular Sequence Data, Fluorescent Antibody Technique, Receptors, Cell Surface, RNA-binding protein, Receptors for Activated C Kinase, Microtubules, Chromatography, Affinity, Gene product, Peptide Elongation Factor 1, GTP-Binding Proteins, Sequence Homology, Nucleic Acid, Two-Hybrid System Techniques, Genetics, Humans, Immunoprecipitation, MRNA transport, Genetics(clinical), Translation factor, RNA, Small Interfering, Annexin A2, In Situ Hybridization, Genetics (clinical), Original Investigation, Ribonucleoprotein, Base Sequence, biology, Nuclear Proteins, Genetic Diseases, X-Linked, Protein phosphatase 2, Molecular biology, Neoplasm Proteins, Ubiquitin ligase, Ribonucleoproteins, Microtubule Proteins, biology.protein, RNA, Nucleophosmin, HeLa Cells, Transcription Factors
Abstract: Opitz BBB/G syndrome (OS) is a heterogenous malformation syndrome mainly characterised by hypertelorism and hypospadias. In addition, patients may present with several other defects of the ventral midline such as cleft lip and palate and congenital heart defects. The syndrome-causing gene encodes the X-linked E3 ubiquitin ligase MID1 that mediates ubiquitin-specific modification and degradation of the catalytic subunit of the translation regulator protein phosphatase 2A (PP2A). Here, we show that the MID1 protein also associates with elongation factor 1α (EF-1α) and several other proteins involved in mRNA transport and translation, including RACK1, Annexin A2, Nucleophosmin and proteins of the small ribosomal subunits. Mutant MID1 proteins as found in OS patients lose the ability to interact with EF-1α. The composition of the MID1 protein complex was determined by several independent methods: (1) yeast two-hybrid screening and (2) immunofluorescence, (3) a biochemical approach involving affinity purification of the complex, (4) co-fractionation in a microtubule assembly assay and (5) immunoprecipitation. Moreover, we show that the cytoskeleton-bound MID1/translation factor complex specifically associates with G- and U-rich RNAs and incorporates MID1 mRNA, thus forming a microtubule-associated ribonucleoprotein (RNP) complex. Our data suggest a novel function of the OS gene product in directing translational control to the cytoskeleton. The dysfunction of this mechanism would lead to malfunction of microtubule-associated protein translation and to the development of OS. Electronic supplementary material The online version of this article (doi:10.1007/s00439-007-0456-6) contains supplementary material, which is available to authorized users.
Published: 2008

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