DOCSLIB.ORG

Multiple Rare Variants in Typical and Atypical Rolandic Epilepsy – a Genetic Analysis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Multiple Rare Variants in Typical and Atypical Rolandic Epilepsy – a Genetic Analysis MULTIPLE RARE VARIANTS IN TYPICAL AND ATYPICAL ROLANDIC EPILEPSY – A GENETIC ANALYSIS Doctoral thesis at the Medical University of Vienna for obtaining the academic degree Doctor of Philosophy Submitted by Mag. rer. nat Eva Maria Reinthaler Supervisor Fritz Zimprich, MD, PhD Department of Neurology Medical University of Vienna Währinger Gürtel 18-20 1090 Vienna, Austria Vienna, August 2014 ii DECLARATION I, Eva Maria Reinthaler, hereby declare that this thesis is my own work accomplished for obtaining the academic degree Doctor of Philosophy at the Medical University of Vienna and has not been submitted to any other University before. The thesis was compiled in a cumulative format using four manuscripts. For all included publications I am a first-shared author. The work was carried out at the Department of Neurology, Medical University of Vienna, Austria in tight collaboration with the Cologne Center for Genomics, University of Cologne, and Department of Neuropediatrics, University Medical Faculty Giessen, Germany. The generation of whole exome sequences and Illumina SNP-array genotyping data was done at the Cologne Center for Genomics with the latter being performed by myself. My main work, however, consisted in the curation of the sample database (DNA isolation, sample preparation), analyzing the data in a candidate gene or genome-wide approach and subsequent validation and segregation experiments (Sanger sequencing, SNP genotyping, quantitative realtime PCR). To increase the power of the analyses the datasets collected at the Department of Neurology, Medical University of Vienna and Department of Neuropediatrics, University Medical Faculty Giessen were merged and published together. Publication 1: published in Nature Genetics Lemke JR*, Lal D*, Reinthaler EM*, et al. Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes. Nat Genet. 2013 Sep;45(9):1067-72. doi: 10.1038/ng.2728. Epub 2013 Aug11. PubMed PMID: 23933819. Reprinted with permission. Publication 2: published in Annals of Neurology Lal D*, Reinthaler EM*, Schubert J*, et al. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol 2014. 2014 May;75(5):788-92. doi: 10.1002/ana.24127. Epub 2014 Apr 14. PubMed PMID: 24591017. Reprinted with permission via RightsLink. Publication 3: published in Human Molecular Genetics Reinthaler EM*, Lal D,* et al. 16p11.2 600 kb Duplications Confer Risk for Typical and Atypical Rolandic Epilepsy. Hum Mol Genet. 2014 Jun16. pii: ddu306. [Epub ahead of print] PubMed PMID: 24939913. Pre-copyedited version reprinted with permission. iii The included manuscript is a pre-copyedited, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The version of record [Reinthaler EM et al. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Hum Mol Genet. 2014 Jun 16. pii: ddu306.] is available online at: http://hmg.oxfordjournals.org/content/early/2014/06/27/hmg.ddu306.long. Publication 4: published in Epilepsia Reinthaler EM*, Lal D,* et al. Analysis of ELP4, SRPX2 and interacting genes in typical and atypical Rolandic epilepsy. Epilepsia. 2014 Jul 3. doi: 10.1111/epi.12712. [Epub ahead of print] PubMed PMID: 24995671. Reprinted with permission via RightsLink. * authors contributed equally to the work iv ACKNOWLEDGEMENTS Many people have directly or indirectly contributed to this thesis in a way they probably didn’t even notice. I cannot thank everyone but I am grateful for all the people, who surrounded me, supported me and with whom I had the pleasure to collaborate. My special and greatest thanks belong to my supervisor Prof. Fritz Zimprich for giving me the opportunity to work on such a collaborative, international research project. I thank him for his assistance, support, patience and belief in me. Many thanks to Dennis, he was my working counterpart and important for long discussions on all the pitfalls of the genetic data we were confronted with. I think we had great fun in studying the genetics of rolandic epilepsy. Still a lot to do! Special thanks also to Prof. Bernd Neubauer of the University Medical Faculty Giessen for his trust in Dennis and me for analyzing some of his more than 25 years old treasure. I specifically want to thank Dr. Thomas Sander from the Cologne Center for Genomics for his contribution to every manuscript and especially for giving me the opportunity for the 2- months exchange at the beginning of my PhD. I think without that I wouldn’t have come so far as this introduction into genome-wide genetics provided me with extremely helpful skills. Of course I would like to thank all the rest of the Cologne Center for Genomics. Further, I like to thank Prof. Alexander Zimprich for providing and supporting me with additional research projects in the field of neurogenetics and keeping me updated with daily news from outside of the PhD-world during lunchtime. I thank my lab colleagues, Christoph, Dora and Gerrit and Chantal from the neighbor lab. I like to thank the founders of the website “what should we call gradschool” for giving me hilarious laughs while the code was (NOT) running. Many thanks to all my friends and my family for being (trying to be) interested and still smiling and nodding although they had no idea what I was talking about in the majority of the time. And finally, a lot of thanks to Jörg, who accompanied and encouraged me through all the years. v TABLE OF CONTENTS DECLARATION iii ACKNOWLEDGEMENTS .................................................................................................v TABLE OF CONTENTS...................................................................................................vi ABSTRACT ....................................................................................................................vii ZUSAMMENFASSUNG ...................................................................................................ix 1 INTRODUCTION........................................................................................................1 1.1 The classification of epilepsies................................................................................1 1.1.1 The spectrum of Idiopathic focal childhood epilepsies .....................................2 1.1.2 Clinical symptomatology of typical and atypical rolandic epilepsy ....................4 1.2 The genetic architecture of complex diseases ........................................................7 1.2.1 Structural genomic variation ..........................................................................11 1.2.2 Overview of Epilepsy Genetics ......................................................................12 1.2.2.1 The genetics of typical and atypical Rolandic Epilepsy................................ 14 1.3 Aim & Objectives ..................................................................................................18 2 RESULTS ................................................................................................................20 2.1 Publication 1: Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes ..................................................................................................................20 2.2 Publication 2: DEPDC5 mutations in genetic focal epilepsies of childhood ...........50 2.3 Publication 3: 16p11.2 600 kb Duplications Confer Risk for Typical and Atypical Rolandic epilepsy..................................................................................................58 2.4 Publication 4: Analysis of ELP4, SRPX2 and interacting genes in typical and atypical Rolandic epilepsy...................................................................................105 3 DISCUSSION.........................................................................................................120 3.1 GRIN2A ..............................................................................................................121 3.2 Copy number variations (16p11.2 microduplication) ...........................................123 3.3 DEPDC5.............................................................................................................126 3.4 Multiple hits in typical and atypical rolandic epilepsy...........................................128 3.5 ELP4 & SRPX2...................................................................................................128 3.6 Summary and Outlook ........................................................................................130 4 SUMMARIZED METHODS ....................................................................................132 4.1 Subjects..............................................................................................................132 4.2 Whole Exome Sequencing..................................................................................132 4.3 Array-Genotyping and CNV calling .....................................................................133 4.4 Sanger Sequencing ............................................................................................134 4.5 Real Time Copy Number Detection.....................................................................134 REFERENCES..............................................................................................................136 ABBREVIATIONS.........................................................................................................146 CURRICULUM VITAE...................................................................................................148
Load more

Recommended publications
  • Acute Knockdown of Depdc5 Leads to Synaptic Defects in Mtor-Related Epileptogenesis
    Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis Antonio de Fusco, Maria Sabina Cerullo, Antonella Marte, Caterina Michetti, Alessandra Romei, Enrico Castroflorio, Stéphanie Baulac, Fabio Benfenati To cite this version: Antonio de Fusco, Maria Sabina Cerullo, Antonella Marte, Caterina Michetti, Alessandra Romei, et al.. Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis. Neurobiology of Disease, Elsevier, In press, 10.1016/j.nbd.2020.104822. hal-02498215 HAL Id: hal-02498215 https://hal.sorbonne-universite.fr/hal-02498215 Submitted on 4 Mar 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Journal Pre-proof Acute knockdown of Depdc5 leads to synaptic defects in mTOR- related epileptogenesis Antonio De Fusco, Maria Sabina Cerullo, Antonella Marte, Caterina Michetti, Alessandra Romei, Enrico Castroflorio, Stephanie Baulac, Fabio Benfenati PII: S0969-9961(20)30097-8 DOI: https://doi.org/10.1016/j.nbd.2020.104822 Reference: YNBDI 104822 To appear in: Neurobiology of Disease Received date: 13 November 2019 Revised date: 2 February 2020 Accepted date: 26 February 2020 Please cite this article as: A. De Fusco, M.S. Cerullo, A. Marte, et al., Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis, Neurobiology of Disease(2020), https://doi.org/10.1016/j.nbd.2020.104822 This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record.
    [Show full text]
  • DEPDC5 Takes a Second Hit in Familial Focal Epilepsy
    DEPDC5 takes a second hit in familial focal epilepsy Matthew P. Anderson J Clin Invest. 2018;128(6):2194-2196. https://doi.org/10.1172/JCI121052. Commentary Loss-of-function mutations in a single allele of the gene encoding DEP domain–containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia–like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies. Find the latest version: https://jci.me/121052/pdf COMMENTARY The Journal of Clinical Investigation DEPDC5 takes a second hit in familial focal epilepsy Matthew P. Anderson Departments of Neurology and Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center, Boston, Massachusetts, USA. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA. These detailed genetic and biochemical correlations in the human tissues then led Loss-of-function mutations in a single allele of the gene encoding DEP them to design tests of causality in a mouse domain–containing 5 protein (DEPDC5) are commonly linked to familial model, in which they reconstituted many focal epilepsy with variable foci; however, a subset of patients presents with features of the human disorder.
    [Show full text]
  • The Genetics of Bipolar Disorder
    Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF.
    [Show full text]
  • Stranded Breaks in Drosophila Youheng Wei1,2†, Lucia Bettedi1†, Chun-Yuan Ting1, Kuikwon Kim1, Yingbiao Zhang1, Jiadong Cai2, Mary a Lilly1*
    RESEARCH ARTICLE The GATOR complex regulates an essential response to meiotic double- stranded breaks in Drosophila Youheng Wei1,2†, Lucia Bettedi1†, Chun-Yuan Ting1, Kuikwon Kim1, Yingbiao Zhang1, Jiadong Cai2, Mary A Lilly1* 1Cell Biology and Neurobiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States; 2College of Bioscience and Biotechnology, Yangzhou University, Yangzhou, China Abstract The TORC1 regulator GATOR1/SEACIT controls meiotic entry and early meiotic events in yeast. However, how metabolic pathways influence meiotic progression in metazoans remains poorly understood. Here we examine the role of the TORC1 regulators GATOR1 and GATOR2 in the response to meiotic double-stranded breaks (DSB) during Drosophila oogenesis. We find that in mutants of the GATOR2 component mio, meiotic DSBs trigger the constitutive downregulation of TORC1 activity and a permanent arrest in oocyte growth. Conversely, in GATOR1 mutants, high TORC1 activity results in the delayed repair of meiotic DSBs and the hyperactivation of p53. Unexpectedly, we found that GATOR1 inhibits retrotransposon expression in the presence of meiotic DSBs in a pathway that functions in parallel to p53. Thus, our studies have revealed a link between oocyte metabolism, the repair of meiotic DSBs and retrotransposon expression. DOI: https://doi.org/10.7554/eLife.42149.001 *For correspondence: [email protected] Introduction †These authors contributed We are interested in understanding how metabolism impacts meiotic progression during oogenesis. equally to this work Target of Rapamycin Complex 1 (TORC1) is a multi-protein complex that functions as a master regu- lator of metabolism (Loewith and Hall, 2011; Laplante and Sabatini, 2012a; Jewell and Guan, Competing interests: The 2013).
    [Show full text]
  • Epileptic Spasms Are a Feature of DEPDC5 Mtoropathy
    Epileptic spasms are a feature of DEPDC5 mTORopathy Gemma L. Carvill, PhD ABSTRACT Douglas E. Crompton, Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic PhD, MBBS spasms. Brigid M. Regan, BSc Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation anal- (Hons) ysis of variants of interest, and detailed clinical assessment of patients with possibly and likely Jacinta M. McMahon, pathogenic variants. BSc (Hons) DEPDC5 Julia Saykally Results: We identified 3 patients with variants in in the cohort of 130 patients with DEPDC5 Matthew Zemel, BS spasms. We also describe 3 additional patients with alterations and epileptic spasms: 2 Amy L. Schneider, MGen from a previously described family and a third ascertained by clinical testing. Overall, we describe DEPDC5 Couns 6 patients from 5 families with spasms and variants; 2 arose de novo and 3 were Leanne Dibbens, PhD familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. Katherine B. Howell, Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de MBBS (Hons), novo mutations, we highlight the relevance of inherited mutations in the setting of a family history BMedSc of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed pheno- Simone Mandelstam, typic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alter- MBChB ations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 Richard J. Leventer, epilepsies more with the recognized features of other mTORopathies. Neurol Genet 2015;1:e17; MBBS, PhD doi: 10.1212/NXG.0000000000000016 A.
    [Show full text]
  • Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
    Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/).
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • Epileptic Spasms Are a Feature of DEPDC5 Mtoropathy
    Epileptic spasms are a feature of DEPDC5 mTORopathy Gemma L. Carvill, PhD ABSTRACT Douglas E. Crompton, Objective: To assess the presence of DEPDC5 mutations in a cohort of patients with epileptic PhD, MBBS spasms. Brigid M. Regan, BSc Methods: We performed DEPDC5 resequencing in 130 patients with spasms, segregation anal- (Hons) ysis of variants of interest, and detailed clinical assessment of patients with possibly and likely Jacinta M. McMahon, pathogenic variants. BSc (Hons) DEPDC5 Julia Saykally Results: We identified 3 patients with variants in in the cohort of 130 patients with DEPDC5 Matthew Zemel, BS spasms. We also describe 3 additional patients with alterations and epileptic spasms: 2 Amy L. Schneider, MGen from a previously described family and a third ascertained by clinical testing. Overall, we describe DEPDC5 Couns 6 patients from 5 families with spasms and variants; 2 arose de novo and 3 were Leanne Dibbens, PhD familial. Two individuals had focal cortical dysplasia. Clinical outcome was highly variable. Katherine B. Howell, Conclusions: While recent molecular findings in epileptic spasms emphasize the contribution of de MBBS (Hons), novo mutations, we highlight the relevance of inherited mutations in the setting of a family history BMedSc of focal epilepsies. We also illustrate the utility of clinical diagnostic testing and detailed pheno- Simone Mandelstam, typic evaluation in characterizing the constellation of phenotypes associated with DEPDC5 alter- MBChB ations. We expand this phenotypic spectrum to include epileptic spasms, aligning DEPDC5 Richard J. Leventer, epilepsies more with the recognized features of other mTORopathies. Neurol Genet 2015;1:e17; MBBS, PhD doi: 10.1212/NXG.0000000000000016 A.
    [Show full text]
  • VIEW Open Access the Role of Ubiquitination and Deubiquitination in Cancer Metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1*
    Sun et al. Molecular Cancer (2020) 19:146 https://doi.org/10.1186/s12943-020-01262-x REVIEW Open Access The role of ubiquitination and deubiquitination in cancer metabolism Tianshui Sun1, Zhuonan Liu2 and Qing Yang1* Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, is considered a hallmark of cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors and metabolic enzymes participate in the modulation of cancer metabolism and thus, metabolic reprogramming is a highly complex process. Recent studies have observed that ubiquitination and deubiquitination are involved in the regulation of metabolic reprogramming in cancer cells. As one of the most important type of post-translational modifications, ubiquitination is a multistep enzymatic process, involved in diverse cellular biological activities. Dysregulation of ubiquitination and deubiquitination contributes to various disease, including cancer. Here, we discuss the role of ubiquitination and deubiquitination in the regulation of cancer metabolism, which is aimed at highlighting the importance of this post-translational modification in metabolic reprogramming and supporting the development of new therapeutic approaches for cancer treatment. Keywords: Ubiquitination, Deubiquitination, Cancer, Metabolic reprogramming Background cells have aroused increasing attention and interest [3]. Metabolic pathways are of vital importance in proliferat- Because of the generality of metabolic alterations in can- ing cells to meet their demands of various macromole- cer cells, metabolic reprogramming is thought as hall- cules and energy [1]. Compared with normal cells, mark of cancer, providing basis for tumor diagnosis and cancer cells own malignant properties, such as increased treatment [1]. For instance, the application of 18F- proliferation rate, and reside in environments short of deoxyglucose positron emission tomography is based on oxygen and nutrient.
    [Show full text]
  • Germline and Somatic Mutations in the MTOR Gene in Focal Cortical Dysplasia and Epilepsy
    Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy Rikke S. Møller, PhD* Sarah Weckhuysen, MD, PhD* ABSTRACT Mathilde Chipaux, MD, Objective: To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) PhD and of germline MTOR mutations in a broad range of epilepsies. Elise Marsan, MSc Methods: We collected 20 blood-brain paired samples from patients with FCD and searched for Valerie Taly, PhD somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were E. Martina Bebin, MD, assessed in a French research cohort of 93 probands with focal epilepsies and in a diagnostic MPA Danish cohort of 245 patients with a broad range of epilepsies. Data sharing among collaborators Susan M. Hiatt, PhD allowed us to ascertain additional germline variants in MTOR. Jeremy W. Prokop, PhD Kevin M. Bowling, PhD Results: We detected recurrent somatic variants (p.Ser2215Phe, p.Ser2215Tyr, and Davide Mei, MSc p.Leu1460Pro) in the MTOR gene in 37% of participants with FCD II and showed histologic Valerio Conti, PhD evidence for activation of the mTORC1 signaling cascade in brain tissue. We further identified Pierre de la Grange, PhD 5 novel de novo germline missense MTOR variants in 6 individuals with a variable phenotype from Sarah Ferrand-Sorbets, focal, and less frequently generalized, epilepsies without brain malformations, to macrocephaly, MD with or without moderate intellectual disability. In addition, an inherited variant was found in Georg Dorfmüller, MD a mother–daughter pair with nonlesional autosomal dominant nocturnal frontal lobe epilepsy. Virginie Lambrecq, MD, Conclusions: Our data illustrate the increasingly important role of somatic mutations of the MTOR PhD gene in FCD and germline mutations in the pathogenesis of focal epilepsy syndromes with and Line H.G.
    [Show full text]
  • Mutations in Mtor Regulator DEPDC5 Cause Focal Epilepsy with Brain
    Mutations in mTOR regulator DEPDC5 cause focal epilepsy with brain malformations Ingrid E Scheffer1, 2, 3 MB BS PhD, Sarah E Heron4, 5 BSc(Hons), PhD, Brigid M Regan1* BSc (Hons), Simone Mandelstam 2, 3, 6* MB ChB, Douglas E Crompton7* MBBS PhD , Bree L Hodgson4, 5 Dip Biomed Sci, Laura Licchetta8 MD, Federica Provini8, 9 MD PhD, Francesca Bisulli8, 9 MD PhD, Lata Vadlamudi1, 10 MB BS PhD, Jozef Gecz11 PhD, Alan Connelly2, 12 PhD, Paolo Tinuper8, 9 MD, Michael G Ricos4, 5 BSc(Hons) PhD, Samuel F Berkovic1 MD FRS, Leanne M Dibbens4, 5 BSc(Hons) PhD * These authors contributed equally 1 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia 2 Florey Institute of Neuroscience and Mental Health, Melbourne, Australia 3 Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia 4 Epilepsy Research Program, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia 5 Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia 6 Department of Radiology, University of Melbourne, Royal Children’s Hospital, Melbourne, Australia 7 Department of Neurology, Northern Health, Melbourne, Victoria, Australia 8 IRCCS, Istituto delle Scienze Neurologiche, University of Bologna, Bologna, Italy 9 Department of Biomedical and Neuromotor Sciences. University of Bologna, Bologna, Italy 10 School of Medicine, The University of Queensland and Department of Neurology, Royal Brisbane and Women’s Hospital, Australia 11 School of Pediatrics and Reproductive Health, The University of Adelaide, Adelaide, Australia 12 Department of Medicine, Austin Health, University of Melbourne, Melbourne, Australia Corresponding author: Professor Ingrid E.
    [Show full text]
  • UC Berkeley UC Berkeley Electronic Theses and Dissertations
    UC Berkeley UC Berkeley Electronic Theses and Dissertations Title Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge Permalink https://escholarship.org/uc/item/1gx9p3q8 Author Rodriguez Perez, Fernando Publication Date 2020 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge By Fernando Rodríguez Pérez A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Molecular and Cell Biology in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, BERKELEY Committee in charge: Professor Michael Rape, Chair Professor Roberto Zoncu Professor Jeffery Cox Professor Daniel Nomura Summer 2020 ABSTRACT Ubiquitin-Dependent Control of Myogenic Development: Mechanistic Insights into Getting Huge, and Staying Huge by Fernando Rodriguez Perez Doctor in Philosophy in Molecular and Cell Biology University of California, Berkeley Professor Michael Rape, Chair Metazoan development is dependent on the robust spatiotemporal execution of stem cell cell-fate determination programs. Although changes in transcriptional and translational landscapes have been well characterized throughout many differentiation paradigms, their regulatory mechanisms remain poorly understood. Ubiquitin has recently been found to be a key modulator of developmental programs. Ubiquitylation of target proteins occurs through a cascade of enzymatic reactions beginning with a ubiquitin activating enzyme (E1) which transfer the ubiquitin moiety to a ubiquitin conjugating enzyme (E2). The reaction is finalized by the transfer of ubiquitin to its target protein by a ubiquitin ligase (E3). Post-translational modification of proteins can lead to several different outcomes, depending on the context of the modification, known as the ubiquitin code.
    [Show full text]