scholarly journals Ribosomopathies: New Therapeutic Perspectives

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2080
Author(s):  
Emilien Orgebin ◽  
François Lamoureux ◽  
Bertrand Isidor ◽  
Céline Charrier ◽  
Benjamin Ory ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Genetic Disorders ◽  
Cell Types ◽  
Treacher Collins Syndrome ◽  
Developmental Defects ◽  
Diamond Blackfan Anemia ◽  
New Therapeutic Approaches ◽  
Multiple Treatments ◽  
New Compounds

Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond–Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.

scholarly journals Ribosomopathies: human disorders of ribosome dysfunction

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3196-3205 ◽  
Author(s):  
Anupama Narla ◽  
Benjamin L. Ebert
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Macrocytic Anemia ◽  
Protein Translation ◽  
Dyskeratosis Congenita ◽  
Treacher Collins Syndrome ◽  
Diamond Blackfan Anemia ◽  
Genes Encoding ◽  
Novel Therapeutic Strategies ◽  
And Function

Abstract Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q− syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.

scholarly journals The Nucleolus ofCaenorhabditis elegans

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Li-Wei Lee ◽  
Chi-Chang Lee ◽  
Chi-Ruei Huang ◽  
Szecheng J. Lo
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Size Control ◽  
Cell Types ◽  
C Elegans ◽  
Homologous Genes ◽  
Early Embryos ◽  
Human Disorders ◽  
Nucleolar Size

Nucleolar size and appearance correlate with ribosome biogenesis and cellular activity. The mechanisms underlying changes in nucleolar appearance and regulation of nucleolar size that occur during differentiation and cell cycle progression are not well understood.Caenorhabditis elegansprovides a good model for studying these processes because of its small size and transparent body, well-characterized cell types and lineages, and because its cells display various sizes of nucleoli. This paper details the advantages of usingC. elegansto investigate features of the nucleolus during the organism's development by following dynamic changes in fibrillarin (FIB-1) in the cells of early embryos and aged worms. This paper also illustrates the involvement of thencl-1gene and other possible candidate genes in nucleolar-size control. Lastly, we summarize the ribosomal proteins involved in life span and innate immunity, and those homologous genes that correspond to human disorders of ribosomopathy.

scholarly journals Proerythroblast Cells of Diamond-Blackfan Anemia Patients With RPS19 and CECR1 Mutations Have Similar Transcriptomic Signature

2021 ◽  
Vol 12 ◽  
Author(s):  
Beren Karaosmanoglu ◽  
M. Alper Kursunel ◽  
Duygu Uckan Cetinkaya ◽  
Fatma Gumruk ◽  
Gunes Esendagli ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Mononuclear Cells ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Ribosomal Protein Genes ◽  
Erythroid Progenitor ◽  
Hematopoietic Stem ◽  
Altered Expression ◽  
Diamond Blackfan Anemia ◽  
Transcriptomic Profile

Diamond Blackfan Anemia (DBA) is an inherited bone marrow (BM) failure syndrome, characterized by a paucity of erythroid differentiation. DBA is mainly caused by the mutations in ribosomal protein genes, hence classified as ribosomopathy. However, in approximately 30% of patients, the molecular etiology cannot be discovered. RPS19 germline mutations caused 25% of the cases. On the other hand, CECR1 mutations also cause phenotypes similar to DBA but not being a ribosomopathy. Due to the blockade of erythropoiesis in the BM, we investigated the transcriptomic profile of three different cell types of BM resident cells of DBA patients and compared them with healthy donors. From BM aspirates BM mononuclear cells (MNCs) were isolated and hematopoietic stem cells (HSC) [CD71–CD34+ CD38mo/lo], megakaryocyte–erythroid progenitor cells (MEP) [CD71–CD34+ CD38hi] and Proerythroblasts [CD71+ CD117+ CD38+] were sorted and analyzed with a transcriptomic approach. Among all these cells, proerythroblasts had the most different transcriptomic profile. The genes associated with cellular stress/immune responses were increased and some of the transcription factors that play a role in erythroid differentiation had altered expression in DBA proerythroblasts. We also showed that gene expression levels of ribosomal proteins were decreased in DBA proerythroblasts. In addition to these, colony formation assay (CFU-E) provided functional evidence of the failure of erythroid differentiation in DBA patients. According to our findings that all patients resembling both RPS19 and CECR1 mutations have common transcriptomic signatures, it may be possible that inflammatory BM niche may have a role in DBA pathogenesis.

Ribosome Dysfunction and Ineffective Hematopoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-11-SCI-11
Author(s):  
Benjamin L. Ebert
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Bone Marrow Failure ◽  
Ribosomal Genes ◽  
Limb Bud ◽  
Refractory Anemia ◽  
Diamond Blackfan Anemia ◽  
Rare Congenital Disorder ◽  
Human Disorders ◽  
And Function

Abstract Abstract SCI-11 The 5q- syndrome and Diamond Blackfan Anemia are related on a molecular level by ribosome dysfunction. The 5q- syndrome is a distinct subtype of myelodysplastic syndrome (MDS) associated with isolated, interstitial deletions of the long arm of Chromosome 5. Diamond Blackfan Anemia is a rare congenital disorder associated with bone marrow failure, craniofacial abnormalities, and limb bud defects. The hematologic phenotype of both diseases includes a severe refractory anemia, macrocytosis, and a deficiency of erythroid precursors. Recent evidence indicates that this erythroid defect is caused by RPS14 deletion in the 5q- syndrome, and by mutation of RPS19 or other ribosomal genes in at least 50% of patients with Diamond Blackfan Anemia. In both diseases, deletion or mutation of one allele of a ribosomal protein leads to defects in pre-rRNA processing and defective production of mature ribosomes. In murine and zebrafish models, haploinsufficiency for ribosomal genes phenocopies the erythroid failure characteristic of the human disorders. While the mechanistic consequences of ribosomal dysfunction have not been fully elucidated, the p53 pathway appears to play a central role. MDM2, an E3 ubiquitin ligase that promotes the degradation of p53, binds to several ribosomal proteins including RPL11. Deficiency of RPS6, and perhaps other ribosomal proteins, causes an accumulation of free RPL11, that binds to MDM2, preventing MDM2 from interacting with p53, thereby leading to an accumulation of p53. Several other genes that are mutated in hematologic disorders are involved in ribosome biogenesis and function, including SBDS, mutated in Shwachman Diamond syndrome; DKC1, mutated in some cases of dyskaratosis congenita; and NPM1, mutated in acute myeloid leukemia and deleted in some cases of MDS. The manner in which each of these genes disrupt ribosome function and cause distinct clinical phenotypes is currently under investigation. Disclosures Ebert: GlaxoSmithKline: Research Funding.

scholarly journals An update on the pathogenesis and diagnosis of Diamond–Blackfan anemia

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1350 ◽  
Author(s):  
Lydie Da Costa ◽  
Anupama Narla ◽  
Narla Mohandas
Keyword(s):  
Genetic Testing ◽  
Congenital Malformations ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Macrocytic Anemia ◽  
Diamond Blackfan Anemia ◽  
Biological Features ◽  
Genes Encoding ◽  
History Of ◽  
Hypoplastic Anemia

Diamond–Blackfan anemia (DBA) is a rare congenital hypoplastic anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic anemia and reticulocytopenia with 50% of cases associated with a variety of congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

scholarly journals L-leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2214-2224 ◽  
Author(s):  
Elspeth M. Payne ◽  
Maria Virgilio ◽  
Anupama Narla ◽  
Hong Sun ◽  
Michelle Levine ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Mrna Translation ◽  
Mtor Pathway ◽  
Developmental Defects ◽  
Diamond Blackfan Anemia ◽  
Common Basis ◽  
Human Cd34 ◽  
Chromosome 5Q ◽  
Cd34 Cells ◽  
The Common

Abstract Haploinsufficiency of ribosomal proteins (RPs) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q [del(5q) MDS]. We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14, respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14-deficient embryos with the amino acid L-leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34+ cells, after shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway, and this is accentuated by L-leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L-leucine. Our studies support the rationale for ongoing clinical trials of L-leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS.

scholarly journals Computational Studies of the Structural Basis of Human RPS19 Mutations Associated With Diamond-Blackfan Anemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Ke An ◽  
Jing-Bo Zhou ◽  
Yao Xiong ◽  
Wei Han ◽  
Tao Wang ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
18S Rrna ◽  
Complex Structure ◽  
Pure Red Cell Aplasia ◽  
Structural Basis ◽  
Hydrophobic Core ◽  
Diamond Blackfan Anemia ◽  
Surface Patches ◽  
Machine Learning Model

Diamond-Blackfan Anemia (DBA) is an inherited rare disease characterized with severe pure red cell aplasia, and it is caused by the defective ribosome biogenesis stemming from the impairment of ribosomal proteins. Among all DBA-associated ribosomal proteins, RPS19 affects most patients and carries most DBA mutations. Revealing how these mutations lead to the impairment of RPS19 is highly demanded for understanding the pathogenesis of DBA, but a systematic study is currently lacking. In this work, based on the complex structure of human ribosome, we comprehensively studied the structural basis of DBA mutations of RPS19 by using computational methods. Main structure elements and five conserved surface patches involved in RPS19-18S rRNA interaction were identified. We further revealed that DBA mutations would destabilize RPS19 through disrupting the hydrophobic core or breaking the helix, or perturb the RPS19-18S rRNA interaction through destroying hydrogen bonds, introducing steric hindrance effect, or altering surface electrostatic property at the interface. Moreover, we trained a machine-learning model to predict the pathogenicity of all possible RPS19 mutations. Our work has laid a foundation for revealing the pathogenesis of DBA from the structural perspective.

scholarly journals Shwachman — Diamond Syndrome: Modern Genetic Aspects of a Ribosomapathy

Doctor Ru ◽  
2020 ◽  
Vol 19 (10) ◽  
pp. 33-36
Author(s):  
M.G. Ipatova ◽  
◽  
Keyword(s):  
High Risk ◽  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Clinical Symptoms ◽  
Genetic Disorders ◽  
Exocrine Insufficiency ◽  
Ribonucleoprotein Complexes ◽  
Shwachman Diamond Syndrome ◽  
Genetically Determined ◽  
Risk Of Cancer

Objective of the Review: To analyse new DNAJC21, EFL1, SRP54 mutations causing ribosome biogenesis defects and presenting with clinical symptoms similar to the symptoms of Shwachman – Diamond syndrome (SDS). Key Points. SDS is a ribosomapathy and is characterised by pancreatic exocrine insufficiency, defective hematopoiesis, musculoskeletal anomalies, and a high risk of myelodysplastic syndrome and acute myeloid leukemia. About 90% of SDS patients have biallelic SBDS mutations. However, 10–20% of patients with a set of symptoms typical of SDS did not have any pathovars in SBDS gene; therefore, we searched for other candidate genes. In addition to SDS, genetic disorders associated with defected maturation, deficient structure or function of ribosomes and ribonucleoprotein complexes include Diamond – Blackfan anemia, cartilage and hair hypoplasy (McKusick type metaphyseal chondrodysplasia), congenital diskeratosis, 5q-syndrome, and others. These syndromes are similar to SDS. All these conditions are associated with medullary deficiency at least in one hematopoiesis chain. All five conditions are associated with a high risk of cancer. Conclusion. SDS is a genetically determined condition belonging to ribosomapathies. Ribosomapathies are caused by mutations in genes that participate in the synthesis of ribosomal proteins and factors, functioning at various stages of their assembly, and give origin to a number of clinical phenotypes, including haematological malignancies and cancer. In clinical practice, SDS is diagnosed on the basis of typical clinical symptoms and if pathogenic SBDS mutations are present. The issue whether SDS is a genetic heterogenetic ribosomapathy or a mutation of other genes causing defective ribosome synthesis and SDS-like symptoms, is disputable and requires further research. Keywords: Shwachman – Diamond syndrome, genes, SBDS, DNAJC21, EFL1, SRP54, ribosomapathy.

scholarly journals p53 activation during ribosome biogenesis regulates normal erythroid differentiation.

Blood ◽  
2020 ◽  
Author(s):  
Salomé Le Goff ◽  
Ismael Boussaid ◽  
Celia Floquet ◽  
Anna Raimbault ◽  
Isabelle Hatin ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Erythroid Differentiation ◽  
Regulatory Function ◽  
Rdna Transcription ◽  
Erythroid Progenitors ◽  
Diamond Blackfan Anemia ◽  
Transcriptional Stress ◽  
P53 Activation ◽  
Erythroid Development

The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.

scholarly journals Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

2021 ◽  
Vol 43 (2) ◽  
pp. 767-781
Author(s):  
Vanessa Pinatto Gaspar ◽  
Anelise Cardoso Ramos ◽  
Philippe Cloutier ◽  
José Renato Pattaro Junior ◽  
Francisco Ferreira Duarte Junior ◽  
...  
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Metabolism ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Cellular Mechanisms ◽  
Cancerous Cell ◽  
First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

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