Journal of Bone Research

ISSN: 2329-8820

Journal of Bone Research
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
Meet Inspiring Speakers and Experts at our 3000+ Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business

Bone Marrow Failure Syndromes: The Ribosomopathies

Arati Khanna-Gupta*

Department of Medicine, Harvard Medical School, USA

Corresponding Author:
Arati Khanna-Gupta
Assistant Professor
Department of Medicine
Harvard Medical School, USA

Received Date: December 30, 2012; Accepted Date: January 02, 2013; Published Date: January 10, 2013

Citation: Khanna-Gupta A (2013) Bone Marrow Failure Syndromes: The Ribosomopathies. J Bone Marrow Res 1:106. doi: 10.4172/2329-8820.1000106

Copyright: © 2013 Khanna-Gupta A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Bone Research


In recent years a number of human diseases associated with dysregulated ribosome biogenesis have been identified and categorized as “ribosomopathies” [1]. Acquired or congenital genetic lesions leading to impaired ribosome biogenesis and function appear to be germane to this class of disorders that include Diamond-Blackfan anemia (DBA), a disorder characterized by pure red cell aplasia, Shwachman-Diamond syndrome (SDS), dyskeratosis congenita (DC), cartilage hair hypoplasia (CHH), Treacher Collins syndrome (TCS), and del (5q), a type of myelodysplastic syndrome (MDS). While each of these disorders is associated with distinct mutations in the ribosome biogenesis pathway (Figure 1), bone marrow failure appears to be a uniformly observed clinical symptom. However, the affected lineages appear to be uniquely syndrome-specific. For example, the erythroid and megakaryocytic lineages are affected in DBA and del (5q) MDS, while neutropenia predominates in SDS.

In recent years a number of human diseases associated with dysregulated ribosome biogenesis have been identified and categorized as “ribosomopathies” [1]. Acquired or congenital genetic lesions leading to impaired ribosome biogenesis and function appear to be germane to this class of disorders that include Diamond-Blackfan anemia (DBA), a disorder characterized by pure red cell aplasia, Shwachman-Diamond syndrome (SDS), dyskeratosis congenita (DC), cartilage hair hypoplasia (CHH), Treacher Collins syndrome (TCS), and del (5q), a type of myelodysplastic syndrome (MDS). While each of these disorders is associated with distinct mutations in the ribosome biogenesis pathway (Figure 1), bone marrow failure appears to be a uniformly observed clinical symptom. However, the affected lineages appear to be uniquely syndrome-specific. For example, the erythroid and megakaryocytic lineages are affected in DBA and del (5q) MDS, while neutropenia predominates in SDS. From the first identification of disruption of RPS19 (ribosomal protein small subunit 19) in a DBA patient by Dahl et al. [2], limited advances have been made in our understanding of the molecular underpinnings of bone marrow failure syndromes [3].


Figure 1: Schematic showing ribosomal RNA processing from the 47S prerRNA species to the mature 18S. 5.8S and 28S rRNAs.

Ribosome Biogenesis and Disease

The human ribosome is a complex Ribonucleoprotein (RNP) supermolecule composed of four ribosomal RNAs and 79 different ribosomal proteins that assemble into a cellular platform for protein synthesis. Ribosome biogenesis occurs in the nucleolus, a nuclear substructure that harbors multiple pre-rRNA genes arranged in tandem. The transcription factors SL1, UBF and RNA polymerase 1, as well as a large family of small nucleolar RNAs, participate in a highly coordinated series of events involving specific cleavage of the pre-rRNP particles (Figure 1). This leads to the formation of the 40S or small ribosomal subunit containing 18S rRNA and the 60S or large ribosomal subunit containing the 28S, 5.8S and 5S rRNA species [4]. Following assembly, the large and small ribosomal subunits are exported to the cytoplasm where protein synthesis ensues. The primary function of ribosomes is to direct the translation of mRNAs into protein. Complete loss of expression of genes encoding ribosomal components has never been described in humans, suggesting that these proteins are so vital to normal cellular function that such mutations are embryonic lethal. However, in Drosophila and mammals, haploinsufficiency of some ribosomal proteins leads to a ribosome deficit that decreases the cell’s translational capacity. In Drosophila, the resultant mutants have a growth restricted phenotype, and are referred to as minute [5]. While it had been known that alterations in ribosome function can alter cell homeostasis, it was not till the discovery of RPS19 being the causative agent of DBA that the role of ribosomes in disease came into focus.

DBA Shows the Way

Haploinsufficiency of Ribosomal Proteins (RP) has been shown to be the common basis for the anemia observed in both DBA and in del (5q) MDS. DBA is a congenital bone marrow failure syndrome characterized by a profound macrocytic anemia. In addition to bone marrow defects, approximately 30-50% of DBA patients have craniofacial, genitourinary, cardiac and limb abnormalities suggesting that DBA is a disease affecting a broad range of developmental features. In addition, DBA shares many of its clinical symptoms, especially erythroblastopenia, with other syndromes such as Shwachman- Diamond syndrome (SDS), cartilage-hair hypoplasia syndrome and dyskeratosis congenita (DC) and del (5q) MDS. More than half the patients with DBA have been shown to have a heterozygous loss of an RP gene, with RPS19, a component of the 40S ribosomal subunit, being the most frequently mutated. The finding that mutations in a ribosomal protein were the underlying cause of the anemia of DBA, was both unexpected and surprising. It remains unclear why defects in ribosomal proteins (RPs) have such a specific and profound effect on erythroid maturation. A number of hypotheses to explain the link between ribosomal protein haploinsufficiency and defective erythropoiesis have been proposed. The most compelling of these proposes that defects associated with ribosomal RNA processing associated with RP haploinsufficiency results in defective ribosome biogenesis, resulting in reduced mRNA translation. Since RPS19 plays a role in the maturation of the 40S ribosomal subunit, haploinsufficiency of this protein in DBA would be expected to result in reduced ribosome levels in all cells. However, since late stage erythroid cells are thought to undergo rapid cell division coupled to an enormous translational demand for globin synthesis, such a decrease may be more acutely disruptive to the translational machinery in erythroid precursors. This hypothesis has recently been tested in both DBA patients and in animal models of DBA treated with the branched chain essential amino acid L-Leucine. L-Leucine positively regulates signaling through the mammalian target of rapamycin complex 1 (mTORC1) pathway, thereby promoting capdependent mRNA translation [6]. The anemia associated with DBA was shown to be partially alleviated in both L-Leucine treated zebrafish and in mice rendered deficient for RPS19 [7,8] suggesting that the effects of RP deficiency can be improved, in part, by elevating mRNA translation. L-Leucine has also been shown to improve the some developmental defects associated with DBA as well as the anemia associated with del (5q) MDS [6,7]. However, whether it can improve the cytopenias associated with other bone marrow failure syndromes remains to be determined.

The first line of therapy for patients with DBA has been treatment with steroids. However, only 80% of patients respond to steroids initially and less than half can be maintained on this therapy for extended periods [8]. Non-responders to steroid therapy undergo regular blood transfusions and require additional iron-chelation therapy to prevent hemochromatosis. The only definitive therapy for DBA patients is allogeneic bone marrow transplantation. However, infections and graftversus host disease contribute to significant morbidity and mortality following transplantation, thus the need for other novel therapies, including the oral use of L-Leucine, clinical trials for which are ongoing in the Czech Republic and about to commence in the United States.

Do Mutant Ribosomes Promote Malignancy

The p53 tumor suppressor pathway is known to play a critical role in the pathophysiology of the ribosomopathies. The leading hypothesis is that ribosomal haploinsufficiency leads to disrupted ribosome biogenesis with an accumulation of free ribosomal proteins that bind MDM2. MDM2 is an E3 Ubiquitin ligase that normally binds to and targets p53 for proteosomal degradation. The consequent accumulation of p53 leads to cell cycle arrest and apoptosis, which ultimately results in anemia. Several animal models have shown that the anemia associated with RP haploinsufficiency is almost completely alleviated in a p53 null background. However, therapies designed to modulate levels of p53 in an RP-deficient background must be viewed with caution as reducing p53 levels may itself contribute to malignancy. In this context, our group and others have shown that p53-independent pathway(s) also contribute to the anemia associated with RP haploinsufficiency. This may provide a window of therapeutic opportunity for bone marrow failure syndromes associated with the up regulation of p53. It should be noted that L-Leucine has recently been shown to deliver its therapeutic benefits in a p53-independent manner, as measured in both zebrafish and in vitro human cell models of DBA [9].

Increased cancer susceptibility has been observed in all the ribosomopathies described to date [10]. While the upregulation of p53 may explain some of the pathological symptoms associated with RP-hapolinsufficiency in DBA, the molecular underpinnings of cancer susceptibility remain unclear.

Deregulation of the translation machinery leading to perturbation of specific mRNA networks associated with cellular transformation, has been touted as an underlying cause for cancer susceptibility in DBA and other bone marrow failure syndromes [11]. The possibility of RPs exerting extra-ribosomal functions and contributing to mRNA translation has been suggested and may contribute to cancer susceptibility. In this context, a recent study has demonstrated that the ribosomal protein RPL38 regulates the translation of the developmentally vital Hox genes, dysregulation of which can lead to malignant transformation [12]. More recently it has been suggested that while ribosomes are thought to be highly conserved mRNA translation machines present in every cell in the body, cells may in fact make ribosomes that differ in composition under different growth conditions [13]. This likely leads to ribosomes with altered translation capacities resulting in differential translation of distinct subpopulation of mRNAs. It is thus tempting to speculate that individual RPs may play a more important role in the translational control of specific mRNAs than previously thought, and that haploinsufficiency of some RPs may contribute to malignant transformation, as has been observed in zebrafish, where haploinsufficiency of a few, but not all, ribosomal proteins leads to tumorigenesis [14].

Concluding Remarks

A central and fundamental role for defective ribosome biogenesis in human disease has now been established. However, a number of questions remain unanswered. First, how do defects in ribosome biosynthesis lead to the pleiotropic clinical manifestations observed in bone marrow failure syndromes? For example, while bone marrow failure is common to both DBA and SDS, patients with the former have severe defects in erythropoiesis while patients with the latter have neutropenia. Since it has been suggested that all ribosomes are not created equal, it is tempting to speculate that different ribosome populations exist under different physiological conditions and that hapolinsufficiency of RPs result in altered mRNA translation in a tissue specific manner, thereby contributing to the specific pathophysiology observed in different ribosomopathies. Second, why is the erythroid lineage specifically targeted in DBA and in del (5q) MDS, despite the fact that ribosomes are required by all cells? And lastly, what is the mechanism underlying the cancer susceptibility in ribosomopathies? Answers to these compelling questions will lead to a better understanding of the biology of ribosomopathies that will allow for the future design of novel and safe therapeutic strategies for the treatment of bone marrow failure syndromes.


Select your language of interest to view the total content in your interested language
Post your comment
Share This Article
Relevant Topics
Disc Abdominal Radiology
Disc Acute Lymphoblastic Leukemia
Disc Acute Megakaryocytic Leukemia
Disc Acute Myelomonocytic Leukemia
Disc Acute Myleoid Leukemia
Disc Adaptive Cell Therapy
Disc Adipose Derived Stem Cells (ASCs)
Disc Advanced Cell Therapy
Disc Advances in Alternative Lung Cancer Treatment
Disc Aleukemic Leukemia
Disc Anaemia Symptoms
Disc Anemia Causes
Disc Aneurysm
Disc Angiogram
Disc Angioplasty
Disc Anti-Cancer Drug
Disc Antiphospholide Antibody Syndrome
Disc Aorta
Disc Arm Transplant
Disc Arteriography or Angiography
Disc Artery
Disc Arthritis
Disc Arthroplasty
Disc Autoimmune Disorder
Disc Autoimmune Haemolytic Anaemia
Disc Autologous Cell
Disc Bladder Carcinoma in Situ
Disc Blood
Disc Blood Cancer
Disc Blood Cancer Symptoms
Disc Blood Clot in Brain
Disc Blood Clots
Disc Blood Group
Disc Blood Lymphocytes
Disc Bone Cancer
Disc Bone Cancer Stages
Disc Bone Grafting
Disc Bone Marrow
Disc Bone Marrow Cancer
Disc Bone Marrow Cancer Survival
Disc Bone Marrow Disease/Disorders
Disc Bone Oncology
Disc Bone Scan and imaging
Disc Bone, Joint, and Muscle Disorders
Disc Bonemarrow Transplant
Disc Brain Transplant
Disc Brain Tumor Treatment
Disc Breast Cancer Surgery
Disc Breast Imaging
Disc Bypass
Disc CT Imaging
Disc Cancer Immunoediting
Disc Cancer Immunology
Disc Cancer Immunotherapies
Disc Cancer Radioimmunotherapy
Disc Cancer Science
Disc Cancer Stem Cells (CSCs)
Disc Cancer Therapies
Disc Cardiovascular Radiology
Disc Carotid Artery Disease
Disc Cell
Disc Cell Biology
Disc Cell Replacemnt Therapy
Disc Cell Therapy Bioprocessing
Disc Cell Therapy Products
Disc Cellular Immunotherapy
Disc Chemotherapies
Disc Chest Radiology
Disc Children orthopaedics
Disc Chronic Lymphocytic Leukemia
Disc Chronic Myleloid Leukemia
Disc Clinical Radiology
Disc Colon Cancer Surgery
Disc Corneal Transplant
Disc Deep Vein Thrombosis
Disc Dendritic Cell Therapy
Disc Dental Stem Cells
Disc Dermatologic Surgery
Disc Diagnostic Radiology
Disc Double Lung Transplant
Disc Embryonic Stem Cells (ESCs)
Disc Emergency Radiology
Disc Endarterectomy
Disc Eosinophilia
Disc Esophageal Cancer
Disc Eye Transplant
Disc Eyeball Transplant
Disc Eyebrow Transplant
Disc Face Transplant
Disc Facial Hair Transplant
Disc Factor XIII
Disc Fecal Transplant
Disc Feline Leukemia Complex
Disc Fetal Stem Cell Therapy
Disc Fluoroscopy Radiology
Disc Fracture
Disc General Radiology
Disc Genitourinary Radiology
Disc Haematologist
Disc Haemolytic Anaemia
Disc Haemolytic Disease of the Newborn
Disc Haemophilia
Disc Haemostasis
Disc Hair Follicle Cells
Disc Hair Transplant
Disc Hairy Cell Leukemia
Disc Head Transplant
Disc Hematology
Disc Hematopoietic Stem Cells (HSCs)
Disc Hyperlipidemia
Disc Iliac Artery
Disc Immune Cell Therapy
Disc Immune Suppression
Disc Immunogene response
Disc Immunosurveillance
Disc Immunotherapeutic agents
Disc Immunotherapy or biologic therapy
Disc Intestine Tranplant
Disc Iron Test
Disc Islet Cell Transplant
Disc Joints and Bones
Disc Juvenile Myelomonocytic Leukaemia
Disc Kidney Cancer Prognosis
Disc Kidney Cancer Surgery
Disc Knee Transplant
Disc Large Cell Lymphoma
Disc Leukemia
Disc Leukemia Drugs
Disc Leukemia Surgery
Disc Leukemia Symptoms
Disc Leukopenia
Disc Live Cell Therapy
Disc Lung Cancer Surgery
Disc Lung Transplantation
Disc Lung Tumor
Disc Lungs Cancer Cure
Disc Lupus
Disc Lymph Node Cancer
Disc Lymphedema
Disc Lymphocytosis
Disc Lymphoma Cancer
Disc Lymphoma Surgery
Disc Lymphoma Symptoms
Disc Lymphosarcoma
Disc Mast Cell Leukemia
Disc Mesenchymal Cells
Disc Mesenchymal Stem Cells
Disc Metastasis
Disc Minimal Invasive surgery
Disc Morbus Hodgkin
Disc Multiple Myeloma
Disc Multipotent Stem Cells
Disc Musculoskeletal Radiology
Disc Myeloid Stem Cells
Disc Myeloma
Disc Nanotechnology, nanomedicine and orthopaedics
Disc Necrosis
Disc Neural Stem Cells (NSCs)
Disc Neural Transplant
Disc Neuroradiology
Disc Neutropenia
Disc Neutrophilic Leukocytosis
Disc Nucleic Acid Research
Disc Oesophageal Cancer Surgery
Disc Oral and Maxillofacial Radiology
Disc Organ Donation
Disc Organ Transplant
Disc Oseophagus Cancer
Disc Osteoimmunology
Disc Ovarian Cancer and Prognosis
Disc Ovary Transplant
Disc Ovation cell therapy
Disc Pain Management and Therapies
Disc Pancreas Transplant
Disc Pancreatic Cancer
Disc Pancreatic Cancer Surgery
Disc Pediatric Leukemia
Disc Pediatric Transplant
Disc Penis Transplant
Disc Plant Stem Cells
Disc Plasma Cell Disorder
Disc Plasma Cell Leukemia
Disc Pluripotent Stem Cells
Disc Prostate Cancer Surgery
Disc Pulmonary Thrombosis
Disc Radiation Therapy
Disc Radiography
Disc Radiology Imaging
Disc Radiotherapy for bone cancer
Disc Recombinant Cytokines
Disc Red Blood Cells
Disc Renal Transplant
Disc Retinal Transplant
Disc Sarcoma Cancer
Disc Sickle Cell Disease
Disc Sickle Cell Trait
Disc Skin Cancer Surgery
Disc Skin Cell Therapy
Disc Skin Transplant
Disc Somatic Cell Therapy
Disc Spinal stenosis
Disc Spleen Cancer
Disc Stem Cell
Disc Stem Cell Preservation
Disc Stem Cell Therapy for Diabetes
Disc Stem Cell Therapy for Osteoarthritis
Disc Stem Cell Transplant
Disc Stomach Cancer Surgery
Disc Surgical Radiology
Disc Systematic Lupus Erythematous
Disc Systems of Immune
Disc T-cell Lymphomas
Disc Tele Radiology
Disc The Musculoskeletal System
Disc Therapeutic Radiology
Disc Thoracic Aortic Aneurysm
Disc Throat Cancer Surgery
Disc Thymus Transplant
Disc Thyroid Cancer Surgery
Disc Tissue Transplant
Disc Totipotent Stem Cells
Disc Transitional cell carcinoma (TCC)
Disc Tumor Immunity
Disc Tumour Immunity
Disc Tumour Immunology
Disc Uterus Transplant
Disc Vascular Disease
Disc Vein
Disc Venous Insufficiency
Disc White Blood Cell
Disc Womb Transplant
Recommended Journals
Disc Leukemia Journal
Disc Radiology Journal
Disc Cancer Journal
Disc Bone Journal
Disc Journal of Blood Research & Hematologic Diseases
Disc Immunooncology Journal
Disc Cell Science Journal
Disc Insights in Stem Cells
Disc Cancer Surgery Journal
Disc Angiology Journal
Disc Blood
Disc Blood Disorders and Transfusion
Disc Transplantation Journal
Disc Stem Cell Journal
  View More»
Recommended Conferences
Disc Leukemia and Bone Marrow Transplantation Conference
November 10-12, 2016 Istanbul, Turkey
Article Tools
Disc Export citation
Disc Share/Blog this article
Article usage
  Total views: 11571
  [From(publication date):
February-2013 - Oct 24, 2016]
  Breakdown by view type
  HTML page views : 7808
  PDF downloads :3763

Post your comment

captcha    Reload  Can't read the image? click here to refresh

OMICS International Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
OMICS International Conferences 2016-17
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

Agri, Food, Aqua and Veterinary Science Journals

Dr. Krish

1-702-714-7001 Extn: 9040

Clinical and Biochemistry Journals

Datta A

1-702-714-7001Extn: 9037

Business & Management Journals


1-702-714-7001Extn: 9042

Chemical Engineering and Chemistry Journals

Gabriel Shaw

1-702-714-7001 Extn: 9040

Earth & Environmental Sciences

Katie Wilson

1-702-714-7001Extn: 9042

Engineering Journals

James Franklin

1-702-714-7001Extn: 9042

General Science and Health care Journals

Andrea Jason

1-702-714-7001Extn: 9043

Genetics and Molecular Biology Journals

Anna Melissa

1-702-714-7001 Extn: 9006

Immunology & Microbiology Journals

David Gorantl

1-702-714-7001Extn: 9014

Informatics Journals

Stephanie Skinner

1-702-714-7001Extn: 9039

Material Sciences Journals

Rachle Green

1-702-714-7001Extn: 9039

Mathematics and Physics Journals

Jim Willison

1-702-714-7001 Extn: 9042

Medical Journals

Nimmi Anna

1-702-714-7001 Extn: 9038

Neuroscience & Psychology Journals

Nathan T

1-702-714-7001Extn: 9041

Pharmaceutical Sciences Journals

John Behannon

1-702-714-7001Extn: 9007

Social & Political Science Journals

Steve Harry

1-702-714-7001 Extn: 9042

© 2008-2016 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version