Case Report: Progressive Familial Intrahepatic Cholestasis Type 3 With
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EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies
Focusing on Personalised Medicine EXTENDED CARRIER SCREENING Peace of Mind for Planned Pregnancies Extended carrier screening is an important tool for prospective parents to help them determine their risk of having a child affected with a heritable disease. In many cases, parents aren’t aware they are carriers and have no family history due to the rarity of some diseases in the general population. What is covered by the screening? Genomics For Life offers a comprehensive Extended Carrier Screening test, providing prospective parents with the information they require when planning their pregnancy. Extended Carrier Screening has been shown to detect carriers who would not have been considered candidates for traditional risk- based screening. With a simple mouth swab collection, we are able to test for over 419 genes associated with inherited diseases, including Fragile X Syndrome, Cystic Fibrosis and Spinal Muscular Atrophy. The assay has been developed in conjunction with clinical molecular geneticists, and includes genes listed in the NIH Genetic Test Registry. For a list of genes and disorders covered, please see the reverse of this brochure. If your gene of interest is not covered on our Extended Carrier Screening panel, please contact our friendly team to assist you in finding a gene test panel that suits your needs. Why have Extended Carrier Screening? Extended Carrier Screening prior to pregnancy enables couples to learn about their reproductive risk and consider a complete range of reproductive options, including whether or not to become pregnant, whether to use advanced reproductive technologies, such as preimplantation genetic diagnosis, or to use donor gametes. -
Molecular Characterization and Structural Implications of 25 New ABCB4 Mutations in Progressive Familial Intrahepatic Cholestasis Type 3 (PFIC3)
European Journal of Human Genetics (2007) 15, 1230–1238 & 2007 Nature Publishing Group All rights reserved 1018-4813/07 $30.00 www.nature.com/ejhg ARTICLE Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3) Dario Degiorgio1, Carla Colombo2, Manuela Seia1, Luigi Porcaro1, Lucy Costantino1, Laura Zazzeron2, Domenico Bordo3 and Domenico A Coviello*,1 1Laboratorio di Genetica Medica, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; 2Centro Fibrosi Cistica, Universita` degli Studi di Milano, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; 3Bioinformatica e Proteomica Strutturale, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal-recessive disorder due to mutations in the ATP-binding cassette, subfamily B, member 4 gene (ABCB4). ABCB4 is the liver-specific membrane transporter of phosphatidylcholine, a major and exclusive component of mammalian bile. The disease is characterized by early onset of cholestasis with high serum c-glutamyltranspeptidase activity, which progresses into cirrhosis and liver failure before adulthood. Presently, about 20 distinct ABCB4 mutations associated to PFIC3 have been described. We report the molecular characterization of 68 PFIC3 index cases enrolled in a multicenter study, which represents the largest cohort of PFIC3 patients screened for ABCB4 mutations to date. We observed 31 mutated ABCB4 alleles in 18 index cases with 29 distinct mutations, 25 of which are novel. Despite the lack of structural information on the ABCB4 protein, the elucidation of the three-dimensional structure of bacterial homolog allows the three-dimensional model of ABCB4 to be built by homology modeling and the position of the mutated amino-acids in the protein tertiary structure to be located. -
Functional Rescue of Misfolding ABCA3 Mutations by Small Molecular Correctors Susanna Kinting, Stefanie Ho¨ Ppner, Ulrike Schindlbeck, Maria E
Human Molecular Genetics, 2018, Vol. 27, No. 6 943–953 doi: 10.1093/hmg/ddy011 Advance Access Publication Date: 9 January 2018 Original Article ORIGINAL ARTICLE Functional rescue of misfolding ABCA3 mutations by small molecular correctors Susanna Kinting, Stefanie Ho¨ ppner, Ulrike Schindlbeck, Maria E. Forstner, Jacqueline Harfst, Thomas Wittmann and Matthias Griese* Department of Pediatric Pneumology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, German Centre for Lung Research (DZL), 80337 Munich, Germany *To whom correspondence should be addressed at: Department of Pediatric Pneumology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, German Centre for Lung Research (DZL), Lindwurmstraße 4, 80337 Munich, Germany. Tel: þ49 89 440057870; Fax: þ49 89 440057872; Email: [email protected] Abstract Adenosine triphosphate (ATP)-binding cassette subfamily A member 3 (ABCA3), a phospholipid transporter in lung lamellar bodies (LBs), is essential for the assembly of pulmonary surfactant and LB biogenesis. Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure. The aim of this study was to prove that disease causing misfolding ABCA3 mutations can be corrected in vitro and to investigate available options for correction. We stably expressed hemagglutinin (HA)-tagged wild-type ABCA3 or variants p.Q215K, p.M760R, p.A1046E, p.K1388N or p.G1421R in A549 cells and assessed correction by quantitation of ABCA3 processing products, their intracellular localization, resembling LB morphological integrity and analysis of functional transport activity. We showed that all mutant proteins except for M760R ABCA3 were rescued by the bithiazole correctors C13 and C17. -
Potentiation of ABCA3 Lipid Transport Function by Ivacaftor and Genistein
Received: 21 February 2019 | Revised: 15 April 2019 | Accepted: 3 May 2019 DOI: 10.1111/jcmm.14397 ORIGINAL ARTICLE Potentiation of ABCA3 lipid transport function by ivacaftor and genistein Susanna Kinting1,2 | Yang Li1 | Maria Forstner1,2 | Florent Delhommel3,4 | Michael Sattler3,4 | Matthias Griese1,2 1Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Abstract LMU Munich, Munich, Germany ABCA3 is a phospholipid transporter implicated in pulmonary surfactant homoeosta‐ 2 Member of the German Center for Lung sis and localized at the limiting membrane of lamellar bodies, the storage compart‐ Research (DZL), Munich, Germany 3Institute of Structural Biology, Helmholtz ment for surfactant in alveolar type II cells. Mutations in ABCA3 display a common Zentrum München, Neuherberg, Germany genetic cause for diseases caused by surfactant deficiency like respiratory distress 4 Center for Integrated Protein Science in neonates and interstitial lung disease in children and adults, for which currently no Munich at Department Chemie, Technical University of Munich, Garching, Germany causal therapy exists. In this study, we investigated the effects of ivacaftor and gen‐ istein, two potentiators of the cystic fibrosis transmembrane conductance regulator Correspondence Matthias Griese, Department of Pediatrics, (CFTR), on ABCA3‐specific lipid transport function. Wild‐type (WT) and functional Dr. von Hauner Children's Hospital, ABCA3 mutations N568D, F629L, G667R, T1114M and L1580P were stably ex‐ University Hospital, LMU Munich, Munich, Germany. pressed in A549 cells. Three‐dimensional modelling predicted functional impairment Email: [email protected]‐muenchen. for all five mutants that was confirmed by in vitro experiments (all <14% of WT func‐ de tional activity). -
Whole-Exome Sequencing Identifies Novel Mutations in ABC Transporter
Liu et al. BMC Pregnancy and Childbirth (2021) 21:110 https://doi.org/10.1186/s12884-021-03595-x RESEARCH ARTICLE Open Access Whole-exome sequencing identifies novel mutations in ABC transporter genes associated with intrahepatic cholestasis of pregnancy disease: a case-control study Xianxian Liu1,2†, Hua Lai1,3†, Siming Xin1,3, Zengming Li1, Xiaoming Zeng1,3, Liju Nie1,3, Zhengyi Liang1,3, Meiling Wu1,3, Jiusheng Zheng1,3* and Yang Zou1,2* Abstract Background: Intrahepatic cholestasis of pregnancy (ICP) can cause premature delivery and stillbirth. Previous studies have reported that mutations in ABC transporter genes strongly influence the transport of bile salts. However, to date, their effects are still largely elusive. Methods: A whole-exome sequencing (WES) approach was used to detect novel variants. Rare novel exonic variants (minor allele frequencies: MAF < 1%) were analyzed. Three web-available tools, namely, SIFT, Mutation Taster and FATHMM, were used to predict protein damage. Protein structure modeling and comparisons between reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. Results: We detected a total of 2953 mutations in 44 ABC family transporter genes. When the MAF of loci was controlled in all databases at less than 0.01, 320 mutations were reserved for further analysis. Among these mutations, 42 were novel. We classified these loci into four groups (the damaging, probably damaging, possibly damaging, and neutral groups) according to the prediction results, of which 7 novel possible pathogenic mutations were identified that were located in known functional genes, including ABCB4 (Trp708Ter, Gly527Glu and Lys386Glu), ABCB11 (Gln1194Ter, Gln605Pro and Leu589Met) and ABCC2 (Ser1342Tyr), in the damaging group. -
Hedgehog-GLI Signalling Promotes Chemoresistance Through The
www.nature.com/scientificreports OPEN Hedgehog‑GLI signalling promotes chemoresistance through the regulation of ABC transporters in colorectal cancer cells Agnese Po1, Anna Citarella1, Giuseppina Catanzaro2, Zein Mersini Besharat2, Sofa Trocchianesi1, Francesca Gianno1, Claudia Sabato2, Marta Moretti2, Enrico De Smaele2, Alessandra Vacca2, Micol Eleonora Fiori3 & Elisabetta Ferretti2,4* Colorectal cancer (CRC) is a leading cause of cancer death. Chemoresistance is a pivotal feature of cancer cells leading to treatment failure and ATP-binding cassette (ABC) transporters are responsible for the efux of several molecules, including anticancer drugs. The Hedgehog-GLI (HH-GLI) pathway is a major signalling in CRC, however its role in chemoresistance has not been fully elucidated. Here we show that the HH-GLI pathway favours resistance to 5-fuorouracil and Oxaliplatin in CRC cells. We identifed potential GLI1 binding sites in the promoter region of six ABC transporters, namely ABCA2, ABCB1, ABCB4, ABCB7, ABCC2 and ABCG1. Next, we investigated the binding of GLI1 using chromatin immunoprecipitation experiments and we demonstrate that GLI1 transcriptionally regulates the identifed ABC transporters. We show that chemoresistant cells express high levels of GLI1 and of the ABC transporters and that GLI1 inhibition disrupts the transporters up-regulation. Moreover, we report that human CRC tumours express high levels of the ABCG1 transporter and that its expression correlates with worse patients’ prognosis. This study identifes a new mechanism where HH‑GLI signalling regulates CRC chemoresistance features. Our results indicate that the inhibition of Gli1 regulates the ABC transporters expression and therefore should be considered as a therapeutic option in chemoresistant patients. Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide and is characterized by resistance mechanisms that lead to disease progression 1. -
Electrophysiological Evidence of Synergistic Auxin Transport by Interacting 2 Arabidopsis ABCB4 and PIN2 Proteins* 3 4 Stephen D
bioRxiv preprint doi: https://doi.org/10.1101/2021.01.25.428116; this version posted January 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Electrophysiological evidence of synergistic auxin transport by interacting 2 Arabidopsis ABCB4 and PIN2 proteins* 3 4 Stephen D. Deslauriers1 and Edgar P. Spalding* 5 6 Department of Botany 7 University of Wisconsin-Madison 8 Madison WI 53706 9 USA 10 11 short title: electrophysiology of ABCB4 and PIN2 proteins 12 13 14 1Present address: 15 Division of Science and Math 16 University of Minnesota, Morris 17 600 East Fourth Street 18 Morris, MN 56267 19 20 *corresponding author [email protected] tel: 608-265-5294 21 22 *The author responsible for distribution of materials integral to the findings 23 presented in this article is Edgar P. Spalding ([email protected]). 24 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.01.25.428116; this version posted January 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 25 26 Abstract 27 To understand why both ATP-binding cassette B (ABCB) and PIN-FORMED (PIN) 28 proteins are required for polar auxin transport through tissues, even though only 29 the latter is polarly localized, we biophysically studied their transport 30 characteristics separately and together by whole-cell patch clamping. ABCB4 and 31 PIN2 from Arabidopsis thaliana expressed in human embryonic kidney cells 32 displayed electrogenic activity when CsCl-based electrolytes were used. -
Categorization and Classification of Different ABCA3 Variants Causing Interstitial Lung Disease
Categorization and classification of different ABCA3 variants causing interstitial lung disease Dissertation der Mathematisch-Naturwissenschaftlichen Fakultät der Eberhard Karls Universität Tübingen zur Erlangung des Doktorgrades Doktor der Naturwissenschaften (Dr. rer. nat.) vorgelegt von Thomas Wittmann aus Neumarkt in der Oberpfalz, Deutschland Tübingen 2016 Gedruckt mit Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Eberhard Karls Universität Tübingen. Tag der mündlichen Qualifikation: 15.07.2016 Dekan: Prof. Dr. Wolfgang Rosenstiel 1. Berichterstatter: Prof. Dr. Dominik Hartl 2. Berichterstatter: Prof. Dr. Andreas Peschel Table of contents Table of contents Table of contents ..........................................................................................................I List of tables.................................................................................................................II List of figures................................................................................................................II Abbreviations ..............................................................................................................III Summary..................................................................................................................... V Zusammenfassung .................................................................................................... VI Publications............................................................................................................. -
Influence of ABCA1 and ABCA7 on the Lipid Microenvironment of the Plasma Membrane
I Influence of ABCA1 and ABCA7 on the lipid microenvironment of the plasma membrane Dissertation zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) im Fach Biologie eingereicht an der Mathematisch-Naturwissenschaftlichen Fakultät I der Humboldt-Universität zu Berlin von Dottore Magistrale in Biotecnologie Industriali Anna Pia Plazzo geb. 17.10.1981 in San Giovanni Rotondo, Italien Präsident der Humboldt-Universität zu Berlin Prof. Dr. Dr. h.c. Christoph Markschies Dekan der Mathematisch-Naturwissenschaftlichen Fakultät I Prof. Dr. Lutz-Helmut Schön Gutachter: 1. Prof. Dr. Andreas Herrmann 2. Prof. Dr. Thomas Günther-Pomorski 3. Prof. Dr. Thomas Eitinger Tag der mündlichen Prüfung: 12.06.2009 II Alla mia famiglia III Zusammenfassung Der ABC-Transporter ABCA1 ist unmittelbar in die zelluläre Lipidhomeostasie einbezogen, in dem er die Freisetzung von Cholesterol an plasmatische Rezeptoren, wie ApoA-I, vermittelt. Trotz intensiver Untersuchungen ist dieser molekulare Mechanismus nicht verstanden. Verschiedene Studien deuten daraufhin, dass durch die Aktivität von ABCA1 bedingte Veränderungen in der Lipidphase der äußeren Hälfte der Plasmamembran (PM) wichtig für die Freisetzung des Cholesterols sind. In der vorliegenden Arbeit wird die Lipidumgebung von ABCA1 in der PM lebender Säugetierzellen unter Anwendung der Fluoreszenzlebenszeitmikroskopie von fluoreszierenden Lipidsonden untersucht. Es wurde eine breite Verteilung der Fluoreszenzlebenszeiten der Sonden gefunden, die sensitiv gegenüber Veränderungen der lateralen und transversalen Organisation der Lipide ist. Im Einklang mit Studien an riesengroßen unilamellaren Vesikeln und Plasmamembranvesikeln weisen unsere Ergebnisse die Existenz einer größeren Vielfalt submikroskopischer Lipiddomänen auf. Die FLIM-Untersuchungen an ABCA1 exprimierenden HeLa-Zellen weisen eine die Lipidphase destabilisierende Funktion des Transportes aus. Dieses wurde unterstützt durch die Lipidanalyse von Fraktionen der PM. -
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Cryo-EM Structure of Lipid Embedded Human ABCA7 at 3.6Å Resolution
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433448; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Cryo-EM structure of lipid embedded human ABCA7 at 3.6Å resolution 2 3 Le Thi My Le1†, James R. Thompson1†, Tomonori Aikawa2, Takahisa Kanikeyo2 & Amer Alam1,* 4 5 6 1The Hormel Institute, University of Minnesota, Austin, Minnesota 59912 7 2Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224 8 †These authors contributed equally to this work 9 *Address correspondence to: Amer Alam, PhD, [email protected] 10 11 12 13 14 15 16 17 18 19 20 21 22 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.01.433448; this version posted March 1, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 23 Abstract 24 Dysfunction of the ATP Binding Cassette (ABC) transporter ABCA7 alters cellular lipid 25 homeostasis and is linked to Alzheimer’s Disease (AD) pathogenesis through poorly understood 26 mechanisms. Here we determined the cryo-electron microscopy (cryo-EM) structure of human 27 ABCA7 in a lipid environment at 3.6Å resolution that reveals an open conformation, despite bound 28 nucleotides, and bilayer lipids traversing the transmembrane domain (TMD). -
ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 172 ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury JENNY M. PEDERSEN ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-8702-7 UPPSALA urn:nbn:se:uu:diva-204200 2013 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Sweden, Friday, September 6, 2013 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Abstract Pedersen, J. M. 2013. ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 172. 67 pp. Uppsala. ISBN 978-91-554-8702-7. Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes.The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed.