The Efficiency of Nonsense-Mediated Mrna Decay Is an Inherent Character and Varies Among Different Cells
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For Immediate Release
FOR IMMEDIATE RELEASE Media contact: Ekaterina Pesheva 617.432.0441 [email protected] WARREN ALPERT FOUNDATION HONORS FIVE PIONEERS IN CYSTIC FIBROSIS -Scientists recognized for identifying faulty gene behind devastating disease, development of precision-targeted therapies The 2018 Warren Alpert Foundation Prize has been awarded to five scientists for transformative discoveries in the fields of genetics, physiology, pulmonology and pharmacology that have led to the development of life-altering precision- targeted treatments for the devastating multiorgan disease cystic fibrosis (CF). The Warren Alpert Foundation, in association with Harvard Medical School, honors trailblazing scientists whose work has improved the understanding, prevention, treatment or cure of human disease. This year’s five honorees will be recognized at a symposium on Oct. 4 at Harvard Medical School. CF affects some 75,000 people in the United States, Canada, Europe and Australia. Life expectancy has improved steadily over the past several decades. The median age of survival in the United States and other developed countries is now estimated to be in the early 40s, compared with a mere few months for children born with CF in the 1950s. Thanks to the discoveries made by the five award recipients, this upward trend is likely to continue, with the advent of new therapies that repair the underlying disease-fueling protein malfunction and, in doing so, stave off organ damage and boost survival. The 2018 Warren Alpert Foundation Prize recipients are: Francis -
The Molecular Basis for Disease Variability in Cystic Fibrosis
Invited Review 1609776 European Journal Eur J Hum Genet 1996;4:65-73 of Human Genetics Batsheva Kerema Eitan Keremb The Molecular Basis for Disease a Department of Genetics, Life Sciences Variability in Cystic Fibrosis Institute, Hebrew University and b Department of Pediatrics, Pulmonary and Cystic Fibrosis Clinic, Shaare Zedek Medical Center, Jerusalem, Israel Key Words Abstract Cystic fibrosis Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in Variable phenotype the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The Male infertility disease is characterized by a wide variability of clinical expression. The clon Variable normal RNA ing of the CFTR gene and the identification of its mutations has promoted extensive research into the association between genotype and phenotype. Sev eral studies showed that there are mutations, like the AF508 (the most com mon mutation worldwide), which are associated with a severe phenotype and there are mutations associated with a milder phenotype. However, there is a substantial variability in disease expression among patients carrying the same mutation. This variability involves also the severity of lung disease. Further more, increased frequencies of mutations are found among patients with incomplete CF expression which includes male infertility due to congenital bilateral absence of the vas deferens. In vitro studies of the CFTR function suggested that different mutations cause different defects in protein produc tion and function. The mechanisms by which mutations disrupt CFTR func tion are defective protein production, processing, channel regulation, and con ductance. In addition, reduced levels of the normal CFTR mRNA are associ ated with the CF disease. -
A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation with Variable Phenotype
A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype Eitan Kerem, MD*; Malka Nissim-Rafinia‡; Zvi Argaman, MD*; Arie Augarten, MD§; Lea Bentur, MDi; Aharon Klar, MD¶; Yaacov Yahav, MD§; Amir Szeinberg, MD§; Ornit Hiba‡; David Branski, MD*; Mary Corey, PhD#; and Batsheva Kerem, PhD‡ ABSTRACT. Objective. Cystic fibrosis (CF) has vari- classified either as a severe or as a mild mutation. able clinical presentation. Disease severity is partially Pediatrics 1997;100(3). URL: http://www.pediatrics.org/ associated with the type of mutation. The aim of this cgi/content/full/100/3/e5; cystic fibrosis, genotype-pheno- study was to report genotype-phenotype analysis of the type correlation, genetics, pancreatic function, pulmonary G85E mutation. function, CFTR mutation. Patients. The phenotype of 12 patients (8 were from the same extended family, and 5 of them were siblings from 2 families) carrying at least one copy of the G85E ABBREVIATIONS. CF, cystic fibrosis; CFTR, cystic fibrosis trans- mutation was evaluated and compared with the pheno- membrane conductance regulator; PI, pancreatic insufficiency; PS, type of 40 patients carrying the two severe mutations, pancreatic sufficiency; PCR, polymerase chain reaction; RT, re- verse transcriptase; FEV , forced expiratory volume in 1 second. W1282X and/or DF508 (group 1), and with 20 patients 1 carrying the splicing mutation, 3849110kb C->T, which was found to be associated with milder disease (group 2). ystic fibrosis (CF), the most common lethal Results. A high phenotypic variability was found autosomal recessive disease among whites, is among the patients carrying the G85E mutation. This caused by defects in the CF transmembrane high variability was found among patients carrying the C same genotype and among siblings. -
Nonsense-Mediated Mrna Decay Affects Nonsense Transcript Levels and Governs Response of Cystic Fibrosis Patients to Gentamicin
Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin Liat Linde, … , Eitan Kerem, Batsheva Kerem J Clin Invest. 2007;117(3):683-692. https://doi.org/10.1172/JCI28523. Research Article Pulmonology Aminoglycosides can readthrough premature termination codons (PTCs), permitting translation of full-length proteins. Previously we have found variable efficiency of readthrough in response to the aminoglycoside gentamicin among cystic fibrosis (CF) patients, all carrying the W1282X nonsense mutation. Here we demonstrate that there are patients in whom the level of CF transmembrane conductance regulator (CFTR) nonsense transcripts is markedly reduced, while in others it is significantly higher. Response to gentamicin was found only in patients with the higher level. We further investigated the possibility that the nonsense-mediated mRNA decay (NMD) might vary among cells and hence governs the level of nonsense transcripts available for readthrough. Our results demonstrate differences in NMD efficiency of CFTR transcripts carrying the W1282X mutation among different epithelial cell lines derived from the same tissue. Variability was also found for 5 physiologic NMD substrates, RPL3, SC35 1.6 kb, SC35 1.7 kb, ASNS, and CARS. Importantly, our results demonstrate the existence of cells in which NMD of all transcripts was efficient and others in which the NMD was less efficient. Downregulation of NMD in cells carrying the W1282X mutation increased the level of CFTR nonsense transcripts and enhanced the CFTR chloride channel activity in response to gentamicin. Together our results suggest that the efficiency of NMD might vary and hence have an important role in governing the response […] Find the latest version: https://jci.me/28523/pdf Research article Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin Liat Linde,1 Stephanie Boelz,2,3 Malka Nissim-Rafinia,1 Yifat S. -
2019 European Cystic Fibrosis Society 16Th ECFS Basic Science Conference
2019 European Cystic Fibrosis Society 16th ECFS Basic Science Conference Conference Programme & Abstract Book Dubrovnik, Croatia Chairpersons Isabelle Callebaut, Carlos Farinha and Martin Mense 27 March – 30 March 2019 2 CONTENTS Page Conference Sponsors 5 Conference Programme 11 Poster Titles & Authors 18 Award Winners 25 Session Abstracts 27 Poster Abstracts 88 3 4 CONFERENCE SPONSORSHIP & SUPPORT The ECFS thanks the following for their support 5 6 WELCOME FROM THE ECFS PRESIDENT Dear Friends and Colleagues, It is a great pleasure to welcome you in Croatia to the 16th European Cystic Fibrosis Conference entirely dedicated to Basic Science. This year we are delighted to welcome Prof. Callebaut as the conference Chairperson who will be supported by Prof. Farinha and Dr. Mense as co-chairpersons. Basic scientific discovery is critical to our understanding of CF, and already we can see new therapies coming through from the hard work of this endeavour. The ECFS is committed to providing you with a platform to discuss your ideas with your colleagues during this important conference which will comprise a series of symposia with invited European and international guest speakers. It is a high priority for us to support the work of scientists in CF and we are proud that this conference is now established as a key annual event in the ECFS programme. Your active participation will contribute to a productive exchange of information and we hope productive collaborations. A very warm welcome to an exciting conference. Isabelle Fajac President European Cystic Fibrosis Society 7 8 WELCOME FROM THE CONFERENCE CHAIRPERSONS A very warm welcome to you to the 16th ECFS Basic Science Conference located, this year, in Croatia. -
A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation with Variable Phenotype
A Missense Cystic Fibrosis Transmembrane Conductance Regulator Mutation With Variable Phenotype Eitan Kerem, MD*; Malka Nissim-Rafinia‡; Zvi Argaman, MD*; Arie Augarten, MD§; Lea Bentur, MDi; Aharon Klar, MD¶; Yaacov Yahav, MD§; Amir Szeinberg, MD§; Ornit Hiba‡; David Branski, MD*; Mary Corey, PhD#; and Batsheva Kerem, PhD‡ ABSTRACT. Objective. Cystic fibrosis (CF) has vari- classified either as a severe or as a mild mutation. able clinical presentation. Disease severity is partially Pediatrics 1997;100(3). URL: http://www.pediatrics.org/ associated with the type of mutation. The aim of this cgi/content/full/100/3/e5; cystic fibrosis, genotype-pheno- study was to report genotype-phenotype analysis of the type correlation, genetics, pancreatic function, pulmonary G85E mutation. function, CFTR mutation. Patients. The phenotype of 12 patients (8 were from the same extended family, and 5 of them were siblings from 2 families) carrying at least one copy of the G85E ABBREVIATIONS. CF, cystic fibrosis; CFTR, cystic fibrosis trans- mutation was evaluated and compared with the pheno- membrane conductance regulator; PI, pancreatic insufficiency; PS, type of 40 patients carrying the two severe mutations, pancreatic sufficiency; PCR, polymerase chain reaction; RT, re- verse transcriptase; FEV , forced expiratory volume in 1 second. W1282X and/or DF508 (group 1), and with 20 patients 1 carrying the splicing mutation, 3849110kb C->T, which was found to be associated with milder disease (group 2). ystic fibrosis (CF), the most common lethal Results. A high phenotypic variability was found autosomal recessive disease among whites, is among the patients carrying the G85E mutation. This caused by defects in the CF transmembrane high variability was found among patients carrying the C same genotype and among siblings. -
Similar Levels of Mrna from the W1282X and the Delta F508 Cystic Fibrosis Alleles, in Nasal Epithelial Cells
Similar levels of mRNA from the W1282X and the delta F508 cystic fibrosis alleles, in nasal epithelial cells. T Shoshani, … , A Tal, B Kerem J Clin Invest. 1994;93(4):1502-1507. https://doi.org/10.1172/JCI117128. Research Article The effect of nonsense mutations on mRNA levels is variable. The levels of some mRNAs are not affected and truncated proteins are produced, while the levels of others are severely decreased and null phenotypes are observed. The effect on mRNA levels is important for the understanding of phenotype-genotype association. Cystic fibrosis (CF) is a lethal autosomal recessive disease with variable clinical presentation. Recently, two CF patients with mild pulmonary disease carrying nonsense mutations (R553X, W1316X) were found to have severe deficiency of mRNA. In the Jewish Ashkenazi CF patient population, 60% of the chromosomes carry a nonsense mutation, W1282X. Patients homozygous for this mutation have severe disease presentation with variable pulmonary disease. The presence of CF transcripts in a group of patients homozygous and heterozygous for this mutation was studied by reverse transcriptase PCR of various regions of the gene. Subsequent hybridization to specific CF PCR probes and densitometry analysis indicated that the CF mRNA levels in patients homozygous for the W1282X mutation are not significantly decreased by the mutation. mRNA levels were compared for patients heterozygous for the W1282X mutation. The relative levels of mRNA with the W1282X, and the delta F508 or the normal alleles, were similar in -
Antisense Oligonucleotide-Based Drug Development for Cystic Fibrosis Patients
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.14.431123; this version posted February 14, 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-NC-ND 4.0 International license. Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10kb C-to-T splicing mutation *Yifat S. Oren1,2, *Michal Irony-Tur Sinai1, $Anita Golec3, $Ofra Barchad-Avitzur2, Venkateshwar Mutyam4, Yao Li4, Jeong Hong5, Efrat Ozeri-Galai2, Aurélie Hatton3, Joel Reiter6, Eric J. Sorscher5 Steve D. Wilton7,8, Eitan Kerem9, Steven M. Rowe4, Isabelle Sermet-Gaudelus3,10-12 and Batsheva Kerem1 * These two authors contributed equally; $ These two authors contributed equally 1Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel 2SpliSense Therapeutics, Jerusalem, Givat Ram, Israel; 3Institut Necker Enfants Malades, INSERM U1151 Université de Paris, Faculté de Médecine Necker, Paris, France; 4Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, United States of America; 5Department of Pediatrics, Emory University, Atlanta, GA, United States of America; 6Pediatric Pulmonary and Sleep Unit, Department of Pediatrics, Hadassah-Hebrew University; Medical Center, Jerusalem, Israel; 7Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, Western Australia, -
THE HUMAN GENOME PROJECT in ISRAEL Research Projects
THE HUMAN GENOME PROJECT IN ISRAEL Research Projects THE HUMAN GENOME PROJECT IN ISRAEL Research Projects JERUSALEM 1998. THE ISRAEL ACADEMY OF SCIENCES AND HUMANITIES TABLE OF CONTENTS Foreword Michael Feldman and Yossi Segal 11 Section 1: Bioinformatics The Weizmann Institute Genome Center Doron Lancet 15 DNA sequencing in the 350 kb olfactory receptor gene cluster on human chromosome 17 Edna Ben-Asher, Gustavo Glusman and Doron Lancet 16 Major activities at the Weizmann Institute Bioinformatics Unit Jaime Prilusky, Vered Chalifa-Caspi, Michael Rebhan, Gustavo Glusman and Dave Hansen 17 Research activity in human genome-related subjects Hanah Margalit 20 Bioinformatics activities Ron Shamir 23 The overexpression of binary tracts in promoter DNA regions Gad Yagil 24 Section 2: Genetic Diseases and Disorders Search for genetic polymorphisms and quantification of human brain and lymphocyte mRNA levels of genes involved in signal transduction Galila Agam and Richard Ebstein 27 Gene mapping and mutation analysis Rivka Carmi and Ruthi Parvari 31 Genetic disease anomalies in the Israeli population Nadine Cohen 35 A genomic human progesterone receptor gene (HPR) mutation leads to increased target gene activation and cosegregates with ethnicity-related risk of sporadic ovarian cancer Ami Fishman 39 The genetic contribution to psychiatric and behavior disorders Amos Frisch 41 Gaucher's disease Amos Frisch 42 The AML1 gene family of transcription factors and Down's syndrome leukemia Yoram Groner 43 Down's syndrome and Alzheimer's disease Yoram Groner 46 Malignant melanoma in different ethnic groups in Israel Mordechai Gutman and J.M. Klausner 49 Amplification of protooncogenes and the expression of the HER2/neu oncogene in invasive breast cancer Mordechai Gutman and J.M. -
38Th EUROPEAN CYSTIC FIBROSIS CONFERENCE
10 – 13 JUNE 2015 BRUSSELS, BELGIUM 38th EUROPEAN CYSTIC FIBROSIS CONFERENCE FINAL PROGRAMME WWW.ECFS.EU/BRUSSELS2015 HIGHLIGHTS OF THE CONFERENCE 38th EUROPEAN CYSTIC FIBROSIS CONFERENCE INTERACTIVE CASE STUDIES FRIDAY 08:30 – 10:00 Each interactive case presents an evolving patient history and a serie of questions designed to test your diagnostic and/or therapeutic skills. You will receive immediate feedback on your answers and treatments choices, along with the opportunity to compare your final score with those of your peers. INTERACTIVE DEBATES - PROS/CONS SATURDAY 09:00 – 10:30 Come discuss the pros and cons, and perhaps even change your viewpoint! LEVEL 0 Copper Hall Gold Hall LEVEL -2 Exhibition & Poster Area MEET THE EXPERTS SESSIONS ECFS TOMORROW LOUNGE THURSDAY & FRIDAY: 07:15 – 08:15 The ECFS Tomorrow initiative is specially ePOSTER CORNERS geared towards assembling those who are In these small interactive breakfast sessions interested in building their future career in the Cystic Fibrosis you will have the opportunity to ask questions community and the ECFS of tomorrow. and discuss a specific topic with experts from The ECFS Tomorrow Lounge will feature: the field. The format encourages a more • An exciting series of mini-workshops aimed at career development personal approach to learning. • A relaxed space for conversation and networking Registration for these sessions is additional to the conference. More information page 71 JOIN US ON LINKEDIN * VISIT US ON FACEBOOK TABLE OF CONTENTS 3 38th EUROPEAN CYSTIC FIBROSIS CONFERENCE