DOCSLIB.ORG

Genetic Modifiers of B-Thalassemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Genetic Modifiers of B-Thalassemia Thalassemia Syndrome • Molecular Basis of Disease Genetic modifiers of b-thalassemia Swee Lay Thein As the defective genes for more and more genetic disorders become unravelled, it is clear that patients with apparently identical genotypes can have many different clinical conditions even in simple monogenic disorders. b thalassemia occurs when there is a deficiency in the synthesis of b globin chains. The clinical manifestations of b tha- lassemia are extremely diverse, spanning a broad spectrum from severe anemia and transfusion-dependency to the asymptomatic state of thalassemia trait. The remark- able phenotypic diversity of the b thalassemias is prototypical of how a wide spectrum of disease severity can be generated in single gene disorders. The most reliable and predictive factor of disease phenotype is the nature of the mutation at the b globin locus itself. However, relating phenotype to genotype is complicated by the complex interaction of the environment and other genetic factors at the secondary and tertiary levels, some implicated from family studies, and others, as yet unidentified. This arti- cle reviews the clinical and hematologic diversity encountered in b thalassemia with an overview of the modifier genes that moderate their disease expression. Key words: b thalassemia, modifier genes. Haematologica 2005; 90:649-660 ©2005 Ferrata Storti Foundation From the Department of Haematological Medicine, he thalassemias refer to a diverse Mediterranean region suggests that the dis- Guy’s, King’s & St Thomas’ School group of hemoglobin disorders char- ease was present as far back as the Neolithic of Medicine, King’s College London, acterized by a reduced synthesis of period.3 More than 200 mutations affecting UK. T one or more of the globin chains (a, b, g, db, the b globin gene are now known to result 1 Correspondence: gdb, d and egdb). b thalassemia occurs in a phenotype of b thalassemia. The most Professor Swee Lay Thein, when there is a deficiency of b globin; typ- common forms are those that are prevalent Department of Haematological ically, it is caused by a direct down-regula- in the malarial tropical and sub-tropical Medicine, Guy’s, King’s & tion in the synthesis of structurally normal regions where a few mutations have St. Thomas’ School of Medicine King’s College London, Denmark Hill b chains. However, a thalassemia pheno- reached high gene frequencies because of Campus, Bessemer Road type can also arise from structural b chain the protection they provide against malaria. London SE5 9PJ. variants if they are synthesized at a reduced In these countries in which b thalassemia is E-mail: [email protected] rate, e.g. Hb E (b26GluÆLys). Alternatively, prevalent, a limited number of alleles (4 to 5) the variants are produced at a normal rate account for 90% or more of the b tha- but are so unstable that they are rapidly lassemias, such that a focused molecular destroyed giving rise to a functional defi- diagnostic approach can be undertaken.4 ciency. The former group of variants is also The epidemiology of the disease, however, referred to as b thalassemic hemoglo- is changing due to a fall in total birth rate, binopathies. The hyperunstable b chain prevention programs and recent population variants act in a dominant negative fashion, movements. In Northern Europe, including causing a disease phenotype even when the UK, the US and Australasia, due to present in a single copy, and hence, have recent population migration, thalassemia been referred to as dominantly inherited b has become an important part of clinical 2 thalassemia. In contrast, typical b tha- practice, and in these regions a much wider lassemia is inherited as a haploinsufficient spectrum of b thalassemia mutations can be Mendelian recessive disease. The tha- encountered. Furthermore, with improved lassemias are the commonest monogenic clinical care and increasing survival of disorders in the world and globally it is esti- affected individuals, complications such as mated that there are 270 million carriers, of chronic liver disease, thrombosis and pul- which 80 million are carriers of b tha- monary hypertension are being increasingly lassemia. Archeological evidence in the recognized in the older patients. haematologica/the hematology journal | 2005; 90(5) | 649 | S.L. Thein et al. cluster A bLCR b 3’HSI 5 4321 e GgAg ybdb 5’ 3’ 10 kb Scale B CCAAT CACCC CACCC 1 30 30 104 105 146 5’ UTR 5’ UTR 5' IVS 1 IVS 2 3' 1 2 3 C ATG GT AG GT AG TAA ATAAA AATAA Promoter 5’ and 3’ UTR RNA + 0 processing b ,b ATG Nonsense Codons Frameshifts G A Figure 1. A. The b globin gene cluster and its flanking regions on chromosome 11p. The e, g, g, d and b globin genes are indicated as gray boxes. The 5' hypersensitive sites (1 to 5) which comprise the bLCR and the 3' hypersensitive sites (3'HS1) are shown as vertical arrows. Hatched boxes represent the olfactory receptor genes. B. General structure of the b globin gene with the 3 exons (gray boxes) and the 2 intervening sequences (IVS1 and IVS2). Conserved sequences (detailed in text) are indicated. The different classes of point mutations causing b thalassemia are shown below the b globin genes. The general structure of the b globin gene is typical 6,7 The b globin gene of the other globin loci (Figure 1B). The genomic sequence spans 1600 bp and codes for 146 amino acids; b globin is encoded by a structural gene found in a the transcribed region is contained in three exons sep- cluster with the other b-like genes spanning 70 Kb on arated by two introns or intervening sequences the short arm of chromosome 11 (11p15.4) (Figure 1). (IVS).The first exon encodes amino acids 1 to 29 G A The cluster contains five functional genes, 5e g- g-yb‚ together with the first two bases for codon 30, exon 2 d-b3’, which are arranged in the order of their develop- encodes part of residue 30 together with amino acids mental expression. Upstream of the entire b globin 31 to 104, and exon 3, amino acids 105 to 146. Exon 2 complex is the locus control region (LCR), which is encodes the residues involved in heme binding and ab essential for the expression of all the genes in the com- dimer formation, while exons 1 and 3 encode for the plex. This region consists of five DNase 1 hypersensi- non-heme-binding regions of the b globin chain. tive (HS) sites (designated HS1 5) distributed between Conserved sequences important for gene function are 6 and 20 Kb 5’ of the e gene. There is one other hyper- found in the 5’ promoter region, at the exon-intron sensitive site ~20 Kb 3’ to the b gene. The two extreme junctions, and in the 3’ untranslated region (3’-UTR) at HS sites flanking the b complex have been suggested to the end of the mRNA sequences. The b globin gene mark the boundaries of the b globin gene domain. The promoter includes 3 positive cis-acting elements: TATA b globin complex is embedded in a cluster of olfactory box (positions –28 to –31), a CCAAT box (positions receptor genes (ORG), part of the family of ~1000 –72 to –76) and duplicated CACCC motifs (proximal genes that are widely distributed throughout the at positions –86 to –90, and distal at position –101 to genome, and expressed in the olfactory epithelium.5 –105). While the CCAAT and TATA elements are | 650 | haematologica/the hematology journal | 2005; 90(5) Genetic modifiers of b-thalassemia found in many eukaryotic promoters, the CACCC silencing and gene competition, mediated by the dif- sequence is found predominantly in erythroid cell-spe- ferent transcription factors in embryonic, fetal and cific promoters. Binding of the Erythroid Krüppel Like adult cells. While the e- and g globin genes are auto- Factor (EKLF) to the CACCC motif appears to be cru- nomously silenced at the appropriate developmental 8,9 cial for normal adult b globin expression. In addition stage, expression of the adult b globin gene depends on to these motifs, the region upstream of the b globin lack of competition from the g gene for the LCR promoter contains two binding motifs for the ery- sequences. This is supported by the down-regulation throid transcription factor GATA 1. The importance of of the cis b gene when g gene is up regulated by point these various 5’ flanking sequences for normal gene mutations in their promoters as illustrated by the non- expression is underscored by b thalassemia arising deletional hereditary persistence of fetal hemoglobin 13 from point mutations in these sequences specifically in (HPFH). Mutations which affect the b promoter, and around the TATA box and the CACCC motifs in which remove competition for the bLCR also, tend to the –80 to –100 region. An enhancer is also found in be associated with variable increases in g and d gene intron 2 and 3’ of the globin gene, 600 to 900 bp down- expression (see later). stream of the poly (A) site.10 The 5’ untranslated region (UTR) occupies a region Molecular basis of b thalassemia of 50 nucleotides between the CAP site, the start of There are two main varieties of b thalassemia alleles; 0 + transcription, and the initiation (ATG) codon. There b thalassemia in which no b globin is produced, and b are two prominently conserved sequences in the 5’ thalassemia in which some b globin is produced, but UTR of the various globin genes (both a and b). One is less than normal. Less severe forms are sometimes des- ++ the CTTCTG hexanucleotide found 8 to 13 ignated b to reflect the minimal deficit in b chain pro- nucleotides downstream from the CAP site, i.e.
Load more

Recommended publications
  • Intergenic Variants of HBS1L-MYB Are Responsible for a Major Quantitative Trait Locus on Chromosome 6Q23 Influencing Fetal Hemoglobin Levels in Adults
    Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults Swee Lay Thein*†‡, Stephan Menzel*, Xu Peng§, Steve Best*, Jie Jiang*, James Close*¶, Nicholas Silver*, Ageliki Gerovasilli*, Chen Ping§, Masao Yamaguchi§, Karin Wahlberg*, Pinar Ulug*, Tim D. Spectorʈ, Chad Garner**, Fumihiko Matsuda§, Martin Farrall††, and Mark Lathrop§ *King’s College London School of Medicine, Division of Gene and Cell Based Therapy, King’s College Hospital, London SE5 9PJ, United Kingdom; †Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London SE5 9PJ, United Kingdom; §Centre National de Ge´notypage, Institut Ge´nomique, Commissariat a`l’Energie Atomique, 91057 Evry, France; ¶SANE/POWIC, Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford OX3 7JX, United Kingdom; ʈTwin Research and Epidemiology Unit, King’s College London, St. Thomas’ Hospital Campus, Lambeth Palace Road, London SE1 7EH, United Kingdom; **Epidemiology Division, Department of Medicine, University of California, Irvine, CA 92697-7550; and ††Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom Edited by Yuet Wai Kan, University of California School of Medicine, San Francisco, CA, and approved May 22, 2007 (received for review December 21, 2006) Individual variation in fetal hemoglobin (HbF, ␣2␥2) response heritability of HbF and FC is estimated to be 89% (5). Cis-acting underlies the remarkable diversity in phenotypic severity of sickle variants and rare mutations at the ␤ globin gene locus explain cell disease and ␤ thalassemia. HbF levels and HbF-associated some of the variability (2), but Ͼ50% of the variance is unlinked quantitative traits (e.g., F cell levels) are highly heritable.
    [Show full text]
  • MILESTONES in the HISTORY of HEMOGLOBIN RESEARCH (In Memory of Professor Titus H.J
    Hemoglobin, 00(0):1–13, (2011) Copyright © Informa Healthcare USA, Inc. ISSN: 0363-0269 print/1532-432X online DOI: 10.3109/03630269.2011.613506 PRESENTED AT THE INTERNATIONAL CONFERENCE ON HEMOGLOBIN DISORDERS KUWAIT, February 5–7th, 2011 MILESTONES IN THE HISTORY OF HEMOGLOBIN RESEARCH (In Memory of Professor Titus H.J. Huisman) Swee Lay Thein1,2 1Department of Molecular Haematology, King’s College London, London, UK 2Department of Haematological Medicine, King’s College Hospital National Health Service Foundation Trust, London, UK Professor Titus H.J. Huisman is best known for his work on hemoglobin (Hb) variants. To date, more than 1,000 Hb variants have been discovered and characterized, of which about one- third were discovered in Titus Huisman’s laboratory at the Medical College of Georgia, Augusta, For personal use only. GA, USA. A registry of these Hb variants and other information, a legacy from Professor Huisman, is now available online, at HbVar database (hhtp://globin.bx.psu.edu/hbvar). During the last century, major developments in Hb research have been made using physical, chemical, physiological and genetic methods. This review highlights the milestones and key developments in Hb research most relevant to hematologists, and that have impacted our understanding and management of the thalassemias and sickle cell disease. Keywords Landmarks in sickle cell disease and thalassemia research INTRODUCTION Hemoglobin Downloaded from informahealthcare.com by Kings College London on 09/20/11 The inherited disorders of hemoglobin (Hb), including sickle cell dis- ease and the thalassemias, are the most common ‘Mendelian’ genetic disorders in the world (1). To date, more than 1,000 Hb variants have been Received 28 May 2011; Accepted 21 June 2011.
    [Show full text]
  • EHA Investor Presentation
    Agios Investor Webcast June 12, 2020 1 Forward Looking Statements This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding Agios’ use of proceeds from the transaction with RPI; developments regarding Agios’ collaboration agreement with Celgene; the potential benefits of mitapivat; Agios’ plans, strategies and expectations for its and its collaborator’s preclinical, clinical and commercial advancement of its drug development, including mitapivat; Agios’ key milestones and guidance for 2020; Agios’ plans regarding future data presentations; Agios’ financial guidance regarding the period in which it will have capital available to fund its operations; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios or its collaborators is developing will successfully commence or complete necessary preclinical and clinical development
    [Show full text]
  • How I Treat the Older Adult with Sickle Cell Disease
    How I Treat Q:A1 Q:1 How I treat the older adult with sickle cell disease Q:2 Swee Lay Thein1 and Jo Howard2 1Sickle Cell Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and 2Department of Haematology, Guy’s and St. Thomas’ Hospitals NHS Foundation Trust, London, United Kingdom Q:3,4,5 With increasing survival, cumulative complications of sickle cell disease (SCD), which develop insidiously over time, are becoming more apparent and common in older patients, particularly those in their fifth decade and beyond. The older patient is also more likely to develop other age-related nonsickle conditions that interact and add to the disease morbidity. A common misconception is that any symptom in a SCD patient is attributable to their SCD and this may lead to delays in diagnosis and appropriate intervention. We recommend regular comprehensive reviews and monitoring for early signs of organ damage and a low threshold for the use of hydroxyurea and blood transfusions as preventative measures for end-organ disease. Treatable comorbidities and acute deterioration should be managed aggressively. Although the primary goal in management of the older adult with SCD is improving anemia and minimizing organ damage, the time has come for us to be more proactive in considering curative therapies previously offered to the younger patient. Curative or experimental interventions should be discussed early, before complications render the patients ineligible for these treatments. (Blood. 2018;00(00):1-11) Introduction We have defined the “older adult” as those 40 years of age or older based on current survival estimates; by the age of 40 years, The majority of newborns in well-resourced countries will now the cumulative organ damage11 will have a significant chronic survive to adulthood.1,2 In 2017, 23% of all patients reported to the health burden.
    [Show full text]
  • ASH Investor Event Presentation
    ASH Investor Event December 8, 2020 1 Forward-Looking Statements This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding the potential benefits of mitapivat; Agios’ plans, strategies and expectations for its and its collaborator’s preclinical, clinical and commercial advancement of its drug development, including mitapivat; Agios’ key milestones for 2020 and 2021; Agios’ plans regarding future data presentations; and the potential benefits of Agios’ strategic plans and focus. The words “anticipate,” “expect,” “goal,” “hope,” “milestone,” “plan,” “potential,” “possible,” “strategy,” “will,” “vision,” and similar expressions are intended to identify forward-looking statements, although not all forward- looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios’ current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios or its collaborators is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios’ product candidates will successfully continue. There can be no guarantee that any positive developments in Agios’ business will result in stock price appreciation. Management's expectations
    [Show full text]
  • Genetic Determinants of Haemolysis in Sickle Cell Anaemia
    research paper Genetic determinants of haemolysis in sickle cell anaemia Jacqueline N. Milton,1 Helen Rooks,2 Summary Emma Drasar,2,3 Elizabeth L. McCabe,1 Haemolytic anaemia is variable among patients with sickle cell anaemia Clinton T. Baldwin,4 Efi Melista,5 Victor R. Gordeuk,6 Mehdi Nouraie,6 and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate Gregory R. Kato,7 Caterina Minniti,7 aminotransferase and bilirubin levels. Using principal component analysis James Taylor,7 Andrew Campbell,8 of these measurements we computed a haemolytic score that we used as a Lori Luchtman-Jones,9 Sohail Rana,6 subphenotype in a genome-wide association study. We identified in one Oswaldo Castro,7,10 Yingze Zhang,11 cohort and replicated in two additional cohorts the association of a single Swee Lay Thein,2,3 Paola Sebastiani,1 nucleotide polymorphism in NPRL3 (rs7203560; chr16p13Á3) À Mark T. Gladwin,11 for the (P = 6Á04 9 10 07). This association was validated by targeted genotyping 11 Walk-PHAAST Investigators and in a fourth independent cohort. The HBA1/HBA2 regulatory elements, 4 Martin H. Steinberg hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of 1 Biostatistics, Boston University, Boston, MA, NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with USA, 2King’s College School of Medicine, rs9926112 (r2 = 1) and in strong LD with rs7197554 (r2 = 0Á75) and 3Molecular Haematology, King’s College London, rs13336641 (r2 = 0Á77); the latter is located between HS-33 and HS-40 sites London, UK, 4Department of Medicine, Boston University School of Medicine, 5Center for and next to a CTCF binding site.
    [Show full text]
  • SICKLE CELL in FOCUS CONFERENCE June 2 - 3, 2016
    THE 10TH SICKLE CELL IN FOCUS CONFERENCE June 2 - 3, 2016 Natcher Conference Center National Heart, Lung and Blood Institute (NHLBI) National Institutes of Health (NIH) Bethesda, near WASHINGTON DC, USA National Heart, Lung, and Blood Institute Table of Contents Welcome From the Directors .................................................4 Program Organizers .............................................................6 Agenda .............................................................................9 Speaker Biographies ..........................................................14 About the South Thames Sickle Cell and Thalassaemia Network (STSTN) ......................................32 Co-hosted by the National Heart, Lung and Blood Institute and the South Thames Sickle Cell & Thalassaemia Network, this two-day, intensive, educational conference highlights and discusses emerging clinical complications and management of sickle cell disease. The clinical and scientific lectures are aimed at consultants, trainee doctors, healthcare professionals involved in the care of patients with sickle cell disease, plus academic researchers in this field. SICKLE CELL IN FOCUS 2016 • 3 PROGRAM DIRECTORS Welcome Hello and a very warm welcome to SCiF 2016, once again hosted by the National Heart, Lung and Blood Institute, NIH in Bethesda. This year we are going global with speakers (Kathy Hassell, Beatrice Gulbis, Dapa Diallo, Jennifer Knight, Anna Barbara Proietti, and Roshan Colah) giving perspectives of how SCD is a health issue in their respective
    [Show full text]
  • 14-H-0172 Courtney D Fitzhugh MD, MCHB, NHLBI* (E
    CLINICAL RESEARCH PROJECT Protocol: 14-H-0172 IND/IDE: Exempt NHLBI Protocol: Pilot Study to Assess Algorithm-Based Hydroxyurea Dosing in Subjects with Sickle Cell Disease Abbreviated Title: Algorithm Hydroxyurea Dosing Keywords: Hydroxyurea, dosing algorithm, fetal hemoglobin, sickle cell disease Principal Investigator and Accountable Investigator: Courtney D Fitzhugh MD, MCHB, NHLBI* (E) Molecular and Clinical Hematology Branch (MCHB) Building 10, Room 9N-112, NHLBI/NIH Bethesda, MD. 20892 Phone: (301) 402-6496 work Email: [email protected] Medically Responsible Investigator: John Tisdale, MD* 301-402-6497 – 10/9N112 NHLBI/MCHB (E) Associate Investigators: Hans Ackerman, MD, DPhil* NIAID/LMVR (E) Jordan Betz, PhD NHLBI/HB (V) Wynona Coles, RRT* NHLBI/MCHB (E) Anna Conrey, CRNP* NHLBI/CHB (E) Deepika Darbari, MD* NHLBI/HB (C) Cameron Fisher NHLBI/SCB (F) Matthew Hsieh, MD* NHLBI/MCHB (E) Mary Jackson, RN* NHLBI/DIR/OCD (E) Dachelle Johnson, PharmD CC/PHARM (E) Mihailo Kaplarevic, PhD NHLBI/DIR/OSD (E) Beth Link, RN* NHLBI/MCHB (E) Laurel Mendelsohn, BS HB, NHLBI (E) Josephine Mgaya HB, NHLBI (C) Jim Nichols, RN* NHLBI/HB (E) Constance Noguchi, PhD NIDDK/MMB (E) Purevdorj Olkhanud, MD, PhD NHLBI/SCB (E) Nermi Parrow, PhD NIDDK/DIR/DDB (F) Staci Martin Peron, PhD NCI/CCR/POB (E) Griffin Rodgers, MD NIDDK/OD (E) Katherine Roskom, RN, MSN* OCD, NHLBI (E) Alan Schechter, MD NIDDK/MMB (E) Tiffani Taylor NHLBI (E) Swee Lay Thein, MD, PhD, DSc NHLBI/HB (E) Kamille West, MD CC/ODDCC/TMD (E) Delon Wilson, MD NHLBI/SCB (F) *denotes who may obtain informed consent 14-H-0172 1 Courtney D.
    [Show full text]
  • Redalyc.Genetic Variants Associated with Fetal Hemoglobin Levels Show
    Biomédica ISSN: 0120-4157 [email protected] Instituto Nacional de Salud Colombia Fong, Cristian; Menzel, Stephan; Lizarralde, María Alejandra; Barreto, Guillermo Genetic variants associated with fetal hemoglobin levels show the diverse ethnic origin in Colombian patients with sickle cell anemia Biomédica, vol. 35, núm. 3, septiembre, 2015, pp. 437-443 Instituto Nacional de Salud Bogotá, Colombia Available in: http://www.redalyc.org/articulo.oa?id=84341144017 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative Biomédica 2015;35:437-43 Genetic variants associated with HbF in Colombia doi: http://dx.doi.org/10.7705/biomedica.v35i3.2573 BRIEF COMMUNICATION Genetic variants associated with fetal hemoglobin levels show the diverse ethnic origin in Colombian patients with sickle cell anemia Cristian Fong1, Stephan Menzel2, María Alejandra Lizarralde1, Guillermo Barreto1 1 Grupo de Genética Molecular Humana, Sección de Genética, Departamento de Biología, Universidad del Valle, Cali, Colombia 2 King’s College London, School of Medicine, The James Black Centre, London, England, United Kingdom Institutions where the research was carried out: This research was carried out at the Laboratorio de Genética Molecular Humana, Departamento de Biología, Universidad del Valle and the Molecular Hematology Lab, School of Medicine, King’s College London Introduction: Fetal hemoglobin is an important factor in modulating the severity of sickle cell anemia. Its level in peripheral blood underlies strong genetic determination. Associated loci with increased levels of fetal hemoglobin display population-specific allele frequencies.
    [Show full text]
  • Molecular Basis of Β Thalassemia and Potential Therapeutic Targets T ⁎ Swee Lay Thein
    Blood Cells, Molecules and Diseases 70 (2018) 54–65 Contents lists available at ScienceDirect Blood Cells, Molecules and Diseases journal homepage: www.elsevier.com/locate/bcmd Review Molecular basis of β thalassemia and potential therapeutic targets T ⁎ Swee Lay Thein Sickle Cell Branch, National Heart, Lung, and Blood Institute/National Institutes of Health, Bethesda, MD, USA ARTICLE INFO ABSTRACT Keywords: The remarkable phenotypic diversity of β thalassemia that range from severe anemia and transfusion-de- β thalassemia pendency, to a clinically asymptomatic state exemplifies how a spectrum of disease severity can be generated in Genotype/phenotype correlation single gene disorders. Fetal hemoglobin While the genetic basis for β thalassemia, and how severity of the anemia could be modified at different levels Genetic prediction of its pathophysiology have been well documented, therapy remains largely supportive with bone marrow transplant being the only cure. Identification of the genetic variants modifying fetal hemoglobin (HbF) pro- duction in combination with α globin genotype provide some prediction of disease severity for β thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Nonetheless, genetic studies have been successful in characterizing the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation. BCL11A has been established as a quantitative repressor, and progress has been made in manipulating its expression using genomic and gene- editing approaches for therapeutic benefits. Recent discoveries and understanding in the mechanisms associated with ineffective and abnormal erythropoiesis have also provided additional therapeutic targets, a couple of which are currently being tested in clinical trials.
    [Show full text]
  • Globin Induction by Decitabine in Human Primary Erythroid Progenitor Cultures
    Journal of Clinical Medicine Communication Proteomic Studies for the Investigation of γ-Globin Induction by Decitabine in Human Primary Erythroid Progenitor Cultures Andria Theodorou 1, Marios Phylactides 1,* , Eleni Katsantoni 2 , Kostas Vougas 2, Spyros D. Garbis 2,3,4, Pavlos Fanis 1,5 , Maria Sitarou 6, Swee Lay Thein 7 and Marina Kleanthous 1 1 Molecular Genetics Thalassaemic Department, Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus; [email protected] (A.T.); [email protected] (P.F.); [email protected] (M.K.) 2 Basic Research Center, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece; [email protected] (E.K.); [email protected] (K.V.); [email protected] (S.D.G.) 3 Division for Cancer Sciences, Southampton General Hospital, University of Southampton, Southampton SO16 6YD, UK 4 Centre for Proteomics Research, Institute for Life Sciences, Highfield Campus, University of Southampton, Southampton SO17 1BJ, UK 5 Molecular Genetics Function and Therapy Department, Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus 6 Thalassaemia Centre, Larnaca General Hospital, Larnaca 6043, Cyprus; [email protected] 7 Sickle cell branch, National Heart, Lung and Blood Institute, The National Institutes of Health, Bethesda, MD 20814, USA; [email protected] * Correspondence: [email protected]; Tel.: +357-22-392657 Received: 13 November 2019; Accepted: 26 December 2019; Published: 3 January 2020 Abstract: Reactivation of γ-globin is considered a promising approach for the treatment of β-thalassemia and sickle cell disease. Therapeutic induction of γ-globin expression, however, is fraught with lack of suitable therapeutic targets. The aim of this study was to investigate the effects that treatment with decitabine has on the proteome of human primary erythroid cells from healthy and thalassemic volunteers, as a means of identifying new potential pharmacological targets.
    [Show full text]
  • The 12Th Sickle Cell in Focus Conference
    The 12th October 22 - 23, 2018 Natcher Conference Center National Heart, Lung, and Blood Institute (NHLBI) National Institutes of Health (NIH) Bethesda, Maryland, USA sponsored by: Welcome Hello and a very warm welcome to the 12th annual Sickle Cell in Focus (SCiF) conference! Program Directors The National Heart, Lung, and Blood Institute (NHLBI) is excited to host the conference on the NIH Campus after a very successful conference in Kingston, Jamaica last year. Historically, investigators and physicians from Asia, Europe, Brazil, Africa, and the Caribbean have participated heavily in SCiF. We hope to continue expanding our capacity to provide consultants, trainee doctors, healthcare professionals, and academics interested in hemoglobin disorders with an opportunity for a comprehensive exploration Swee Lay Thein, M.B., B.S., of current medical trends and research results in SCD globally. F.R.C.P., F.R.C.Path., D.Sc. Senior Investigator and Chief As always, the conference will have a mix of updates on management Laboratory of Sickle Cell Genetics and therapies, and exploring what’s new in technology for translational and Pathophysiology diagnostics. With improved survival for affected newborns, physicians are faced with an increasing number of adults with SCD. We have focused on a Sickle Cell Branch few of the complications in older adults, including pain, VTE’s, hepatopathy, NHLBI, National Institutes of Health red blood cell allo-immunization and iron overload. There will also be an update on the curative therapies, the in’s and out’s of gene therapy - gene correction and gene addition. We will revisit the cerebrovascular complications, and not just overt disease, in a whole session by 3 eminent speakers.
    [Show full text]