DOCSLIB.ORG

Do Ribosomopathies Explain Some Cases of Common Variable Immunodeficiency?Cei 4280 96..103

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Do Ribosomopathies Explain Some Cases of Common Variable Immunodeficiency?Cei 4280 96..103 Clinical and Experimental Immunology ORIGINAL ARTICLE doi:10.1111/j.1365-2249.2010.04280.x Do ribosomopathies explain some cases of common variable immunodeficiency?cei_4280 96..103 S. Khan,*† J. Pereira,‡ P. J. Darbyshire,§ Summary S. Holding,¶ P. C. Doré,¶ The considerable clinical heterogeneity of patients with common variable W. A. C. Sewell† and A. Huissoon** immunodeficiency disorders (CVID) shares some similarity with bone- *Department of Immunology, Frimley Park Hospital, Frimley, Surrey, †Centre for marrow failure disorders such as Diamond–Blackfan anaemia (DBA) and Immunoglobulin Therapy, Scunthorpe General Shwachman–Diamond syndrome (SDS), now recognized as defects in ribo- Hospital, Scunthorpe, §Paediatric Oncology and some biogenesis or ribosomopathies. The recognition of a patient with DBA Haematology, Birmingham Children’s Hospital, who subsequently developed CVID lends support to our previous finding of a **Department of Immunology, Birmingham heterozygous mutation in the SBDS gene of SBDS in another CVID patient, Heartlands Hospital, Birmingham, ¶Department suggesting that ribosome biogenesis defects are responsible for a subset of of Immunology, Hull Royal Infirmary, Hull, UK, CVID. Genetic defects in the ribosomal translational machinery responsible and ‡Centro Hospitalar de Coimbra, Unidade de for various bone marrow failure syndromes are recognized readily when they Hematologia Molecular, Coimbra, Portugal manifest in children, but diagnosing these in adults presenting with complex phenotypes and hypogammaglobulinaemia can be a challenge. In this per- spective paper, we discuss our clinical experience in CVID patients with ribosomopathies, and review the immunological abnormalities in other con- ditions associated with ribosomal dysfunction. With genetic testing available for various bone marrow failure syndromes, our hypothesis that ribosomal abnormalities may be present in patients with CVID could be proved in future Accepted for publication 14 September 2010 studies by testing for mutations in specific ribosomal genes. New knowledge Correspondence: S. Khan, Department of might then be translated into novel therapeutic strategies for patients in this Immunology, Frimley Park Hospital NHS group of immunodeficiency disorders. Foundation Trust, Portsmouth Road, Frimley, Camberley, Surrey GU16 7UJ, UK. Keywords: bone marrow failure, common variable immunodeficiency, E-mail: [email protected] Diamond–Blackfan anaemia, ribosome, ribosomopathy insufficiency [4]. There is emerging evidence that loss of Introduction Shwachman–Bodian–Diamond syndrome (SBDS) protein Common variable immunodeficiency disorders (CVID) affects haematopoeisis and numbers of circulating B lym- comprise a range of hypogammaglobulinaemias, for which a phocytes [5]. Craniofacial malformation syndromes such as small number of genetic defects have been identified [1–3]. Treacher–Collins syndrome, caused by haploinsufficiency of However, these account for only a small proportion of cases the treacle protein, also affect the cells of the immune system of CVID, and the majority of patients have no identified [6], and a broader immunological defect has been described genetic cause. A number of bone marrow failure syndromes in the congenital anaemia of Diamond–Blackfan syndrome are now recognized to be due to defects in ribosome biogen- (Diamond–Blackfan anaemia: DBA) [7]. The 5q- syndrome, esis with mutations in genes coding for ribosomal proteins. a somatically acquired deletion of chromosome 5q and a Various immunological abnormalities are evident in these subtype of myelodysplastic syndrome, leads to haploinsuffi- syndromes and provide proof that failure of optimal ribo- ciency of a ribosomal protein that is also implicated in DBA. some function, ‘ribosomopathies’, can also affect cells of the The active eukaryotic ribosome, the site of protein synthe- immune system. sis, is composed of 40S and 60S subunits. Formation of the These syndromes are heterogeneous in their clinical active complex requires synthesis and assembly of core ribo- presentations: for example, patients with Shwachman– somal proteins, ribosomal RNAs, small nucleolar RNAs and Diamond syndrome (SDS) with confirmed mutations in the several other associated proteins (see Fig. 1). This process SBDS gene (Chr7q11) may not have all the characteristic begins in the nucleolus and the preribosomal units are features of neutropenia, skeletal defects and pancreatic exported into the cytoplasm for final steps in the maturation 96 © 2010 The Authors Clinical and Experimental Immunology © 2010 British Society for Immunology, Clinical and Experimental Immunology, 163: 96–103 Ribosomopathies and common variable immunodeficiency complete deletion of one RPS19 allele) generated enormous interest in the clinical effects of disordered ribosome biosyn- thesis [8,9]. Mutations in the RPS19 gene prevent assembly of the 40S ribosomal subunit, but account for only 25% of DBA patients [9]. However, to our knowledge, there have been no reports of failure of antibody production in DBA. We present our clinical experience with the report of the first case of DBA who subsequently developed antibody deficiency, consistent with a new diagnosis of CVID, with complications of bronchiectasis and managed on immuno- globulin therapy. The previous case of CVID with mutation in the SBDS gene of SDS has been discussed briefly with additional data, as a detailed report was published in a pre- vious issue of this Journal [10]. In the final part of this perspective paper, we review the immunological abnormali- Fig. 1. An overview of the biogenesis of the eukaryotic ribosome. ties beginning to emerge in ribosomopathy syndromes. Synthesis of ribosomal proteins and assembly of the mature eukaryotic ribosome has several step: (1) DNA transcription and RNA processing; (2) translation of ribosomal RNA (rRNA); (3) Clinical experience of ribosomopathies and modification and processing by small nucleolar RNPs (snoRNPs) and hypogammaglobulinaemia Rnase; (4) formation of immature large and small ribosomal subunits and exit from nucleolus; and (5) formation of mature eukaryotic DBA and CVID ribosome[8]. The 60S subunit has a cleft for tRNA and amino acids Clinical synopsis including investigations. A 22-year-old from the endoplasmic reticulum (ER) are translated into protein. rRNA, ribosomal RNA; mRNA, messenger RNA; tRNA, transfer RNA; female presented with bronchiectasis and hypo- AAA, amino acids. gammaglobulinemia. DBA had been diagnosed at 1 year of age and required treatment with corticosteroids and blood transfusions until the age of 6 years. There were no associ- of ribosomes [8]. The exact functions of many of these pro- ated skeletal, cardiac or congenital defects. Over the next 3 teins remain unknown. Some ribosomal proteins are now years she suffered from recurrent sinusitis, otitis media, chest known to have extraribosomal functions; for example, the infections (sputum cultures positive for Moraxella catarrha- SBDS protein has a role in stabilizing the mitotic spindle. lis and Haemophilus species) and viral warts. Immunological abnormalities in ribosomopathies may She has a sister with features of DBA – low haemoglobin at therefore provide clues as to how ribosomal proteins can 10·4 g/dl, raised mean corpuscular volume (MCV), lym- shape the immune system. phopenia, elevated fetal haemoglobin (HbF) (3%), high According to internationally accepted criteria, the diagno- erythrocyte adenosine deaminase (eADA) levels, mildly sis of CVID remains one of exclusion. The currently identi- reduced T cell numbers and slight reduction in proliferative fied four genetic mutations (ICOS, CD19, TACI, BAFFR) responses to standard mitogens. The sister’s immunoglobu- account for fewer than a fifth of cases, with no consensus on lin levels, including functional antibody levels, are normal which genetic testing should be undertaken in most cases and she has not required any specific therapy for her [1]. The current European Society of Immunodeficiency anaemia. (ESID)/Pan-American Group for Immunodeficiency Investigations in infancy showed a normocytic anaemia, (PAGID) criteria for CVID include:‘probable’ CVID in those normal serum immunoglobulins [IgG 7·3 g/l (normal range aged > 2 years with low immunoglobulin (Ig)G and another 3·0–10·5), IgA 0·28 g/l (0·1–1·2), IgM 1·07 g/l (0·3–1·5)] and low isotype level (IgA or IgM) with absent vaccine responses; good vaccine responses to conjugated Haemophilus influen- and ‘possible’ CVID in those with low immunoglobulin of zae type b and unconjugated pneumococcal polysaccharide any isotype with absent vaccine responses where other vaccines. By the age of 9, serum IgG levels had dropped to causes of hypogammaglobulinaemia have been excluded [2]. 4·94 g/l (normal range 6·0–13·0). Lymphocyte proliferation Additional similarities with ribosomopathies and CVID responses to phytohaemagglutinin, pokeweed mitogen, patients include heterogeneous presentations with T cell OKT3, tetanus, varicella and herpes antigens were reduced. defects, cytopenias and malignancies [1–3]. Intravenous immunoglobulin (IVIG) replacement therapy The initial description of DBA was of a congenital eryth- was commenced, and stopped after 8 years for reassessment roblastopenia characterized by an early arrest of pre- of immune function. Four years later, she had persistent erythroblast differentiation. The first report of loss-of- anaemia (Hb 10·0 g/dl, MCV 95·6fl) and low IgG (3·37 g/l), function mutations in a gene coding for a ribosomal protein
Load more

Recommended publications
  • Is Swachman-Diamond Syndrome a Ribosomopathy?
    Downloaded from genesdev.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Of blood, bones, and ribosomes: is Swachman-Diamond syndrome a ribosomopathy? Arlen W. Johnson1,3 and Steve R. Ellis2 1Section of Molecular Genetics and Microbiology, The University of Texas at Austin, Austin Texas 78712, USA; 2Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA Mutations in the human SBDS (Shwachman-Bodian-Di- regulation (Ambekar et al. 2010), and stabilizing the amond syndrome) gene are the most common cause of mitotic spindle (Austin et al. 2008). This has led to the Shwachman-Diamond syndrome, an inherited bone mar- suggestion that SBDS is a multifunctional protein, which row failure syndrome. In this issue of Genes & Develop- in turn has led to considerable discussion about which, ment, Finch and colleagues (pp. 917–929) establish that if any, clinical features of SDS are due to defects in SBDS functions in ribosome synthesis by promoting the ribosome production, and which can be attributed to recycling of eukaryotic initiation factor 6 (eIF6) in a GTP- a role for SBDS in other cellular pathways. The study by dependent manner. This work supports the idea that Finch et al. (2011) in this issue of Genes & Development a ribosomopathy may underlie this syndrome. clearly defines a role of SBDS in ribosome synthesis in mammalian cells. This knowledge represents an impor- tant step in ongoing efforts to equate clinical features of SDS with cellular processes affected by loss-of-function Shwachman-Diamond syndrome (SDS) is an inherited mutations in SBDS.
    [Show full text]
  • DKC1 Is a Transcriptional Target of GATA1 and Drives Upregulation of Telomerase Activity Ferrata Storti Foundation in Normal Human Erythroblasts
    Hematopoiesis ARTICLE DKC1 is a transcriptional target of GATA1 and drives upregulation of telomerase activity Ferrata Storti Foundation in normal human erythroblasts Laura A. Richards,1* Ashu Kumari,1* Kathy Knezevic,2 Julie AI Thoms,2,3 Georg von Jonquieres,1 Christine E. Napier,1 Zara Ali,4 Rosemary O’Brien,1 Jonathon Marks-Bluth,2 Michelle F. Maritz,1 Hilda A Pickett,5 Jonathan Morris,6 John E. Pimanda2,3 and Karen L. MacKenzie1,4,7,8 1Children’s Cancer Institute Australia, Randwick; 2Adult Cancer Program, Prince of Wales 3 Haematologica 2020 Clinical School, Lowy Cancer Research Centre, UNSW, Sydney; School of Medical Sciences, UNSW, Sydney; 4Cancer Research Unit, Children’s Medical Research Institute, Volume 105(6):1517-1526 Westmead; 5Telomere Length Regulation Unit, Children’s Medical Research Institute, Westmead; 6The University of Sydney School of Medicine, Kolling Institute of Medical Research, St Leonards; 7School of Women’s and Children’s Health, UNSW, Sydney and 8Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia *LAR and AK contributed equally as co-first authors ABSTRACT elomerase is a ribonucleoprotein complex that maintains the length and integrity of telomeres, and thereby enables cellular proliferation. TUnderstanding the regulation of telomerase in hematopoietic cells is relevant to the pathogenesis of leukemia, in which telomerase is constitu- tively activated, as well as bone marrow failure syndromes that feature telomerase insufficiency. Past studies showing high levels of telomerase in human erythroblasts and a prevalence of anemia in disorders of telomerase insufficiency provide the rationale for investigating telomerase regulation in erythroid cells.
    [Show full text]
  • Translation Factors and Ribosomal Proteins Control Tumor Onset and Progression: How?
    Oncogene (2014) 33, 2145–2156 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Translation factors and ribosomal proteins control tumor onset and progression: how? F Loreni1, M Mancino2,3 and S Biffo2,3 Gene expression is shaped by translational control. The modalities and the extent by which translation factors modify gene expression have revealed therapeutic scenarios. For instance, eukaryotic initiation factor (eIF)4E activity is controlled by the signaling cascade of growth factors, and drives tumorigenesis by favoring the translation of specific mRNAs. Highly specific drugs target the activity of eIF4E. Indeed, the antitumor action of mTOR complex 1 (mTORc1) blockers like rapamycin relies on their capability to inhibit eIF4E assembly into functional eIF4F complexes. eIF4E biology, from its inception to recent pharmacological targeting, is proof-of-principle that translational control is druggable. The case for eIF4E is not isolated. The translational machinery is involved in the biology of cancer through many other mechanisms. First, untranslated sequences on mRNAs as well as noncoding RNAs regulate the translational efficiency of mRNAs that are central for tumor progression. Second, other initiation factors like eIF6 show a tumorigenic potential by acting downstream of oncogenic pathways. Third, genetic alterations in components of the translational apparatus underlie an entire class of inherited syndromes known as ‘ribosomopathies’ that are associated with increased cancer risk. Taken together, data suggest that in spite of their evolutionary conservation and ubiquitous nature, variations in the activity and levels of ribosomal proteins and translation factors generate highly specific effects. Beside, as the structures and biochemical activities of several noncoding RNAs and initiation factors are known, these factors may be amenable to rational pharmacological targeting.
    [Show full text]
  • RPSA, a Candidate Gene for Isolated Congenital Asplenia, Is Required for Pre-Rrna Processing and Spleen Formation in Xenopus John N
    © 2018. Published by The Company of Biologists Ltd | Development (2018) 145, dev166181. doi:10.1242/dev.166181 RESEARCH REPORT RPSA, a candidate gene for isolated congenital asplenia, is required for pre-rRNA processing and spleen formation in Xenopus John N. Griffin1, Samuel B. Sondalle2, Andrew Robson1, Emily K. Mis1, Gerald Griffin1, Saurabh S. Kulkarni1, Engin Deniz1, Susan J. Baserga2,3,* and Mustafa K. Khokha1,2,* ABSTRACT 2004; Henras et al., 2008; Woolford and Baserga, 2013). Production A growing number of tissue-specific inherited disorders are starts in the nucleolus, with transcription of pre-ribosomal RNAs associated with impaired ribosome production, despite the (pre-rRNA), and continues through a series of carefully regulated universal requirement for ribosome function. Recently, mutations in cleavages and ribonucleoparticle assembly steps to ultimately RPSA, a protein component of the small ribosomal subunit, were produce the large 60S ribonucleoprotein subunit (LSU, an discovered to underlie approximately half of all isolated congenital intricate complex of 46 ribosomal proteins and the 28S, 5.8S and asplenia cases. However, the mechanisms by which mutations in this 5S rRNAs) and the small 40S subunit (SSU, 33 ribosomal proteins ribosome biogenesis factor lead specifically to spleen agenesis and the 18S rRNA) (Armistead and Triggs-Raine, 2014; Henras remain unknown, in part due to the lack of a suitable animal model for et al., 2008; Sondalle and Baserga, 2014). Along with cytoplasmic study. Here we reveal that RPSA is required for normal spleen translation factors, the LSU and SSU form a functional ribosome. development in the frog, Xenopus tropicalis. Depletion of Rpsa in It is not surprising that defects in ribosome production or function early embryonic development disrupts pre-rRNA processing and are detrimental to health.
    [Show full text]
  • Ribosomal Protein L10: from Function to Dysfunction
    cells Review Ribosomal Protein L10: From Function to Dysfunction Daniela Pollutri 1,2 and Marianna Penzo 1,2,* 1 Department of Experimental, Diagnostic and Specialty Medicine Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; [email protected] 2 Center for Applied Biomedical Research (CRBA), Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy * Correspondence: [email protected]; Tel.: +39-051-214-3521 Received: 15 October 2020; Accepted: 16 November 2020; Published: 19 November 2020 Abstract: Eukaryotic cytoplasmic ribosomes are highly structured macromolecular complexes made up of four different ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs), which play a central role in the decoding of genetic code for the synthesis of new proteins. Over the past 25 years, studies on yeast and human models have made it possible to identify RPL10 (ribosomal protein L10 gene), which is a constituent of the large subunit of the ribosome, as an important player in the final stages of ribosome biogenesis and in ribosome function. Here, we reviewed the literature to give an overview of the role of RPL10 in physiologic and pathologic processes, including inherited disease and cancer. Keywords: RPL10; ribosome; cancer; ribosomopathy; rare disease; translation; protein synthesis 1. Introduction Eukaryotic cytoplasmic ribosomes are highly structured macromolecular complexes made up of four different ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs), which play a central role in the decoding of genetic code for the synthesis of new proteins. These two distinct yet complementary functions are separated into the two ribosomal subunits: the 40S (or small) and the 60S (or large) subunits, respectively.
    [Show full text]
  • SCIENCE CHINA the Role of Ribosomal Proteins in the Regulation
    SCIENCE CHINA Life Sciences • REVIEW • July 2016 Vol.59 No.7: 656–672 doi: 10.1007/s11427-016-0018-0 The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity Xilong Xu1, Xiufang Xiong1* & Yi Sun1,2,3‡ 1Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang 310029, China; 2Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Zhejiang 310029, China; 3Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor MI 48109, USA Received March 15, 2016; accepted April 6, 2016; published online June 12, 2016 Ribosomal proteins (RPs), the essential components of the ribosome, are a family of RNA-binding proteins, which play prime roles in ribosome biogenesis and protein translation. Recent studies revealed that RPs have additional extra-ribosomal func- tions, independent of protein biosynthesis, in regulation of diverse cellular processes. Here, we review recent advances in our understanding of how RPs regulate apoptosis, cell cycle arrest, cell proliferation, neoplastic transformation, cell migration and invasion, and tumorigenesis through both MDM2/p53-dependent and p53-independent mechanisms. We also discuss the roles of RPs in the maintenance of genome integrity via modulating DNA damage response and repair. We further discuss mutations or deletions at the somatic or germline levels of some RPs in human cancers as well as in patients of Diamond-Blackfan ane- mia and 5q- syndrome with high susceptibility to cancer development. Moreover, we discuss the potential clinical application, based upon abnormal levels of RPs, in biomarker development for early diagnosis and/or prognosis of certain human cancers.
    [Show full text]
  • Small and Large Ribosomal Subunit Deficiencies Lead to Distinct Gene Expression Signatures That Reflect Cellular Growth Rate
    Small and Large Ribosomal Subunit Deficiencies Lead to Distinct Gene Expression Signatures that Reflect Cellular Growth Rate The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Cheng, Ze et al. “Small and Large Ribosomal Subunit Deficiencies Lead to Distinct Gene Expression Signatures that Reflect Cellular Growth Rate.” Molecular Cell 73 (2019): 36-47 © 2019 The Author(s) As Published 10.1016/j.molcel.2018.10.032 Publisher Elsevier BV Version Author's final manuscript Citable link https://hdl.handle.net/1721.1/125016 Terms of Use Creative Commons Attribution-NonCommercial-NoDerivs License Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Cell Manuscript Author . Author manuscript; Manuscript Author available in PMC 2020 January 03. Published in final edited form as: Mol Cell. 2019 January 03; 73(1): 36–47.e10. doi:10.1016/j.molcel.2018.10.032. Small and large ribosomal subunit deficiencies lead to distinct gene expression signatures that reflect cellular growth rate Ze Cheng1, Christopher Frederick Mugler1,2, Abdurrahman Keskin3, Stefanie Hodapp3, Leon Yen-Lee Chan1,2, Karsten Weis2, Philipp Mertins4, Aviv Regev4, Marko Jovanovic3, and Gloria Ann Brar1,*,# 1Department of Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA 2Department of Biology, Institute of Biochemistry, ETH, CH-8093 Zurich, Switzerland 3Department of Biological Sciences, Columbia University, New York, NY, 10027, USA 4Broad Institute of Harvard and MIT, Cambridge, MA, 02139, USA Summary: Levels of the ribosome, the conserved molecular machine that mediates translation, are tightly linked to cellular growth rate.
    [Show full text]
  • A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans
    HIGHLIGHTED ARTICLE INVESTIGATION A Novel Ribosomopathy Caused by Dysfunction of RPL10 Disrupts Neurodevelopment and Causes X-Linked Microcephaly in Humans Susan S. Brooks,*,1 Alissa L. Wall,†,1 Christelle Golzio,† David W. Reid,‡ Amalia Kondyles,† Jason R. Willer,† Christina Botti,* Christopher V. Nicchitta,‡,§ Nicholas Katsanis,† and Erica E. Davis†,2 *Department of Pediatrics, Rutgers Biomedical and Health Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, and †Center for Human Disease Modeling, ‡Department of Biochemistry, and §Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710 ORCID IDs: 0000-0002-1618-7127 (S.B.); 0000-0002-2412-8397 (E.D.) ABSTRACT Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant.
    [Show full text]
  • UTR Gata1s Splice Mutation
    The N-terminal domain of human GATA1 prevents dyserythropoietic anemia and megakaryocyte dysplasia in vivo Jacob Zucker1,2, Constance Temm5, Magdalena Czader5 and Grzegorz Nalepa1,2,3,4* 1Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA. 2Division of Pediatric Hematology-Oncology, Bone Marrow Failure Program, Riley Hospital for Children, Indianapolis, Indiana, USA. 3Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. 4Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 5Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. *Corresponding author. Grzegorz Nalepa, Indiana University School of Medicine, Department of Pediatrics, Division of Pediatric Hematology-Oncology, Herman B Wells Center for Pediatric Research, 1044 W. Walnut Street, R4-421, Indianapolis, Indiana 46202, USA. Phone: 317.278.9846; Fax: 317.274.0138; E-mail: [email protected]. Running title: GATA1 5-UTR mutation in human disease Word count: 1193 _________________________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Zucker, J., Temm, C., Czader, M., & Nalepa, G. (2016). A Child With Dyserythropoietic Anemia and Megakaryocyte Dysplasia Due to a Novel 5′UTR GATA1s Splice Mutation. Pediatric Blood & Cancer, 63(5), 917–921. http://doi.org/10.1002/pbc.25871 Key Points 1. Novel germline mutation within the 5’-UTR of GATA1 disrupts splicing of full-length GATA1, causing congenital dyserythropoiesis and megakaryocyte dysplasia 2. Human full-length GATA1 isoform is produced exclusively in erythroblasts and megakaryocytes to orchestrate RBC and platelet production Abstract Inherited mutations in the X-linked hematopoietic transcription factor GATA1 lead to a wide range of blood disorders, from Diamond-Blackfan anemia to myelodysplastic syndrome.
    [Show full text]
  • Molecular Basis of the Human Ribosomopathy Shwachman-Diamond Syndrome
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Apollo Advances in Biological Regulation 67 (2018) 109e127 Contents lists available at ScienceDirect Advances in Biological Regulation journal homepage: www.elsevier.com/locate/jbior Molecular basis of the human ribosomopathy Shwachman- Diamond syndrome * Alan J. Warren a, b, c, a Cambridge Institute for Medical Research, Cambridge, UK b The Department of Haematology, University of Cambridge, Cambridge, UK c Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK article info abstract Article history: Mutations that target the ubiquitous process of ribosome assembly paradoxically cause Received 4 September 2017 diverse tissue-specific disorders (ribosomopathies) that are often associated with an Accepted 5 September 2017 increased risk of cancer. Ribosomes are the essential macromolecular machines that read Available online 6 September 2017 the genetic code in all cells in all kingdoms of life. Following pre-assembly in the nucleus, precursors of the large 60S and small 40S ribosomal subunits are exported to the cyto- Keywords: plasm where the final steps in maturation are completed. Here, I review the recent insights SBDS into the conserved mechanisms of ribosome assembly that have come from functional DNAJC21 eIF6 characterisation of the genes mutated in human ribosomopathies. In particular, recent Shwachman-Diamond syndrome advances in cryo-electron microscopy, coupled with genetic, biochemical and prior Ribosome structural data, have revealed that the SBDS protein that is deficient in the inherited Myelodysplastic syndromes leukaemia predisposition disorder Shwachman-Diamond syndrome couples the final step in cytoplasmic 60S ribosomal subunit maturation to a quality control assessment of the structural and functional integrity of the nascent particle.
    [Show full text]
  • Inflammasome Regulates Hematopoiesis Through Cleavage
    Inflammasome Regulates Hematopoiesis through Cleavage of the Master Erythroid Transcription Factor GATA1 Sylwia Tyrkalska, Ana Pérez-Oliva, Lola Rodríguez-Ruiz, Francisco Martínez-Morcillo, Francisca Alcaraz-Pérez, Francisco Martínez-Navarro, Christophe Lachaud, Nouraiz Ahmed, Timm Schroeder, Irene Pardo-Sánchez, et al. To cite this version: Sylwia Tyrkalska, Ana Pérez-Oliva, Lola Rodríguez-Ruiz, Francisco Martínez-Morcillo, Francisca Alcaraz-Pérez, et al.. Inflammasome Regulates Hematopoiesis through Cleavage of the Mas- ter Erythroid Transcription Factor GATA1. Immunity, Elsevier, 2019, Epub ahead of print. 10.1016/j.immuni.2019.05.005. hal-02148333 HAL Id: hal-02148333 https://hal.archives-ouvertes.fr/hal-02148333 Submitted on 5 Jun 2019 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. Manuscript 1 INFLAMMASOME REGULATES HEMATOPOIESIS THROUGH CLEAVAGE 2 OF THE MASTER ERYTHROID TRANSCRIPTION FACTOR GATA1 3 4 Sylwia D. Tyrkalska1,&,#, Ana B. Pérez-Oliva1,#,*, Lola Rodríguez-Ruiz1, Francisco J. 5 Martínez-Morcillo1, Francisca Alcaraz-Pérez2, Francisco J. Martínez-Navarro1, 6 Christophe Lachaud3, Nouraiz Ahmed4, Timm Schroeder4, Irene Pardo-Sánchez1, 7 Sergio Candel1,$, Azucena López-Muñoz1, Avik Choudhuri5, Marlies P. Rossmann5, 8 Leonard I. Zon5,6, María L. Cayuela2, Diana García-Moreno1,*, Victoriano Mulero1,* ,¶ 9 1Universidad de Murcia, IMIB-Arrixaca, Murcia, Spain.
    [Show full text]
  • The Ribosomopathy Paradox
    FEBS Letters 588 (2014) 1491–1500 journal homepage: www.FEBSLetters.org Review Diverse diseases from a ubiquitous process: The ribosomopathy paradox ⇑ Joy Armistead a, Barbara Triggs-Raine a,b, a Department of Biochemistry and Medical Genetics, The University of Manitoba, 745 Bannatyne Ave., Winnipeg, MB R3E 0J9, Canada b The Manitoba Institute of Child Health, 715 McDermot Ave., Winnipeg, MB R3E 3P4, Canada article info abstract Article history: Collectively, the ribosomopathies are caused by defects in ribosome biogenesis. Although these dis- Received 9 January 2014 orders encompass deficiencies in a ubiquitous and fundamental process, the clinical manifestations Revised 8 March 2014 are extremely variable and typically display tissue specificity. Research into this paradox has offered Accepted 12 March 2014 fascinating new insights into the role of the ribosome in the regulation of mRNA translation, cell Available online 19 March 2014 cycle control, and signaling pathways involving TP53, MYC and mTOR. Several common features Edited by Ulrike Kutay of ribosomopathies such as small stature, cancer predisposition, and hematological defects, point to how these diverse diseases may be related at a molecular level. Ó 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Keywords: Ribosomopathy Ribosome biogenesis Tissue specificity IRES elements 1. Introduction through cleavage and modification events, ensuring equimolar amounts of these rRNA species. The 5S rRNA is transcribed inde- The ribosomopathies are a diverse group of disorders which, pendently by RNA polymerase III in the nucleoplasm, undergoing despite their heterogeneity at a clinical level, affect the same its own maturation pathway before re-importation into the biochemical process.
    [Show full text]