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Ribosomopathies: Molecular Basis of Disease and Therapeutic Strategies

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (1 January 2022) | Viewed by 10051

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Special Issue Editors

Dr. Amee J. George

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Guest Editor

The John Curtin School of Medical Research, The Australian National University, Canberra 0200, Australia
Interests: ribosomopathies; ribosome biogenesis; nucleolus; nucleolar stress; high-throughput screening; drug discovery

Prof. Dr. Ross Hannan

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Guest Editor

The Division of Genome Science and Cancer, The John Curtin School of Medical Research, The Australian National University, Acton, Canberra 2601, Australia
Interests: ribosomal RNA; rDNA transcription; RNA polymerase 1; chromatin biology; ribosomopathies; drug development; preclinical models of cancer; early phase clinical trials
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Special Issue Information

Dear Colleagues,

Ribosomopathies are a group of rare, genetically inherited diseases which are linked to impairments in ribosome biogenesis and function. While many of these diseases lead to defects in cellular growth and proliferation and bone marrow failure, intriguingly, they demonstrate different tissue specificities which results in a diverse range of clinical presentations.Furthermore, and somewhat paradoxically, patients with these syndromes are also predisposed to an increased risk of developing cancer. While there has been much progress in the clinical management of these diseases, many of the treatments are highly invasive, therefore, new therapeutics and treatment strategies are required for long-term management. It has been known for decades that the nucleolus, a subnuclear organelle located within the nucleus of cells drives the process of ribosome biogenesis; it has only been more recently that other roles of nucleolus have been identified, including mechanisms which monitor for cellular changes that can interfere with ribosome biogenesis and make decisions about cell fate. The aberrant activation of these mechanisms has been implicated, at least in part, in the molecular pathogenesis of these diseases.

This special issue on ribosomopathies will invite original research articles, reviews and short communications on areas of ribosomopathies which span the molecular genetics and pathogenesis of these group of diseases, through to novel and new treatment strategies for these patients.

Dr. Amee J. George
Prof. Dr. Ross Hannan
Guest Editors

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Keywords

Ribosomopathies
Ribosome biogenesis
Ribosomal proteins
mRNA translation
Nucleolar surveillance pathway
Inherited bone marrow failure
Rare diseases
Therapeutics

Published Papers (3 papers)

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Research

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12 pages, 1751 KiB

Open AccessArticle

GATA-1 Defects in Diamond–Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease

by Birgit van Dooijeweert, Sima Kheradmand Kia, Niklas Dahl, Odile Fenneteau, Roos Leguit, Edward Nieuwenhuis, Wouter van Solinge, Richard van Wijk, Lydie Da Costa and Marije Bartels

Genes 2022, 13(3), 447; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030447 - 28 Feb 2022

Cited by 9 | Viewed by 3119

Abstract

Diamond–Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management. Full article

(This article belongs to the Special Issue Ribosomopathies: Molecular Basis of Disease and Therapeutic Strategies)

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Review

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11 pages, 510 KiB

Open AccessReview

Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

by Jeffrey M. Lipton, Christine L. S. Molmenti, Pooja Desai, Alexander Lipton, Steven R. Ellis and Adrianna Vlachos

Genes 2022, 13(1), 56; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010056 - 26 Dec 2021

Cited by 10 | Viewed by 3810

Abstract

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of a class of disorders known as ribosomopathies. Most cases result from loss of function mutations or deletions in 1 of 23 genes encoding either a small or large subunit-associated ribosomal protein (RP), resulting in RP haploinsufficiency. DBA is characterized by red cell hypoplasia or aplasia, poor linear growth and congenital anomalies. Small case series and case reports demonstrate DBA to be a cancer predisposition syndrome. Recent analyses from the Diamond Blackfan Anemia Registry of North America (DBAR) have quantified the cancer risk in DBA. These studies reveal the most prevalent solid tumor, presenting in young adults and in children and adolescents, to be colorectal cancer (CRC) and osteogenic sarcoma, respectively. Of concern is that these cancers are typically detected at an advanced stage in patients who, because of their constitutional bone marrow failure, may not tolerate full-dose chemotherapy. Thus, the inability to provide optimal therapy contributes to poor outcomes. CRC screening in individuals over the age of 50 years, and now 45 years, has led to early detection and significant improvements in outcomes for non-DBA patients with CRC. These screening and surveillance strategies have been adapted to detect familial early onset CRC. With the recognition of DBA as a moderately penetrant cancer risk syndrome a rational screening and surveillance strategy will be implemented. The downstream molecular events, resulting from RP haploinsufficiency and leading to cancer, are the subject of significant scientific inquiry. Full article

(This article belongs to the Special Issue Ribosomopathies: Molecular Basis of Disease and Therapeutic Strategies)

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11 pages, 667 KiB

Open AccessReview

Signaling Pathways That Regulate Normal and Aberrant Red Blood Cell Development

by Mark C. Wilkes, Aya Shibuya and Kathleen M. Sakamoto

Genes 2021, 12(10), 1646; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101646 - 19 Oct 2021

Cited by 3 | Viewed by 2332

Abstract

Blood cell development is regulated through intrinsic gene regulation and local factors including the microenvironment and cytokines. The differentiation of hematopoietic stem and progenitor cells (HSPCs) into mature erythrocytes is dependent on these cytokines binding to and stimulating their cognate receptors and the signaling cascades they initiate. Many of these pathways include kinases that can diversify signals by phosphorylating multiple substrates and amplify signals by phosphorylating multiple copies of each substrate. Indeed, synthesis of many of these cytokines is regulated by a number of signaling pathways including phosphoinositide 3-kinase (PI3K)-, extracellular signal related kinases (ERK)-, and p38 kinase-dependent pathways. Therefore, kinases act both upstream and downstream of the erythropoiesis-regulating cytokines. While many of the cytokines are well characterized, the nuanced members of the network of kinases responsible for appropriate induction of, and response to, these cytokines remains poorly defined. Here, we will examine the kinase signaling cascades required for erythropoiesis and emphasize the importance, complexity, enormous amount remaining to be characterized, and therapeutic potential that will accompany our comprehensive understanding of the erythroid kinome in both healthy and diseased states. Full article

(This article belongs to the Special Issue Ribosomopathies: Molecular Basis of Disease and Therapeutic Strategies)

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