Special Issue "Genetics and Genomics of Erythrocytosis"

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

Deadline for manuscript submissions: 30 October 2021.

Special Issue Editors

Prof. Dr. Nataša Debeljak
E-Mail Website
Guest Editor
Medical Centre for Molecular Biology (MCMB), Faculty of Medicine, Institute of Biochemistry, University of Ljubljana Vrazov trg 2, SI-1000 Ljubljana, Slovenia
Interests: congenital erythrocytosis (ECYT); idiopathic erythrocytosis (IE); erythropoiesis; molecular pathways; genetic background; molecular diagnosis
Prof. Dr. Mary Frances McMullin
E-Mail Website
Co-Guest Editor
Centre for Medical Education, Queen’s University Belfast, Belfast BT9 7BL, UK
Interests: myeloproliferative disorders; polycythaemia vera; idiopathic erythrocytosis; acute myeloid leukaemia; chronic myeloid leukaemia; clinical trials
Prof. Dr. Celeste Bento
E-Mail Website
Co-Guest Editor
1. Department of Hematology, Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal
2. Research Centre for Anthropology and Health (CIAS), Department of Life Sciences, University of Coimbra, 3004-531 Coimbra, Portugal
Interests: red blood cell disorders; hemoglobinopathies; congenital erythrocytosis
Dr. Sylvie Hermouet
E-Mail Website
Co-Guest Editor
CRCINA, Inserm U1232, Université de Nantes, Institut de Recherche en Santé 2 (IRS-2), 22 Boulevard Benoni Goullin, 44200 Nantes, France
Interests: inflammation; genetic defects; myeloproliferative neoplasms (MPN); multiple myeloma (MM); monoclonal gammopathy of undetermined significance (MGUS)

Special Issue Information

Dear Colleagues,

Erythrocytosis is a blood disorder characterized by an increased mass of red blood cells. The most common causes of erythrocytosis are acquired and caused by diseases and conditions associated with hypoxemia or overexpression of erythropoietin. More rarely, erythrocytosis has a known genetic background. Polycythaemia Vera (PV) is caused by somatic mutations, mainly in JAK2, while congenital or familial erythrocytosis (ECYT) is a rare disorder caused by germline mutations in several genes. ECYT1 is associated with EPOR gene variants, ECYT2-5 with defects in the oxygen sensing pathways (variants in VHL, EGLN1, EPAS1, EPO) and ECYT6-8 with increased affinity of haemoglobin for oxygen (variants in HBB, HBA1, HBA2, BPGM). Many patients with idiopathic erythrocytosis remain undiagnosed, indicating that the genes and molecular pathways involved in disease development are not yet fully understood.

This Special Issue on the Genetics and Genomics of Erythrocytosis will include a selection of original papers and reviews focusing on the genetic background and molecular mechanisms involved in the development of erythrocytosis, including polycythaemia vera and congenital erythrocytosis. Recent advances in genetic and clinical diagnostics will be reviewed. Current and new regulatory networks, epigenetic origins, and pathophysiological mechanisms will be discussed.

Prof. Dr. Nataša Debeljak
Prof. Dr. Celeste Bento
Dr. Sylvie Hermouet
Prof. Dr. Mary Frances McMullin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • erythrocytosis
  • erythropoiesis
  • gene regulatory networks
  • molecular pathways
  • epigenetics
  • genetic diagnosis
  • clinical diagnosis
  • pathophysiologic mechanisms

Published Papers (4 papers)

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Research

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Article
Integrative Map of HIF1A Regulatory Elements and Variations
Genes 2021, 12(10), 1526; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101526 - 28 Sep 2021
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Abstract
Hypoxia-inducible factor (HIF) family of transcription factors (HIF1A, EPAS1, and HIF3A) are regulators of the cellular response to hypoxia. They have been shown to be involved in development of various diseases such as cancer, diabetes, and erythrocytosis. A complete map of connections between [...] Read more.
Hypoxia-inducible factor (HIF) family of transcription factors (HIF1A, EPAS1, and HIF3A) are regulators of the cellular response to hypoxia. They have been shown to be involved in development of various diseases such as cancer, diabetes, and erythrocytosis. A complete map of connections between HIF family of genes with various omics types has not yet been developed. The main aim of the present analysis was to construct the integrative map of genomic elements associated with HIF1A gene and prioritize potentially deleterious variants. Various genomic databases and bioinformatics tools were used, including Ensembl, MirTarBase, STRING, Cytoscape, MethPrimer, CADD, SIFT, and UALCAN. Integrative HIF1A gene map was visualized and includes transcriptional and post-transcriptional regulators, downstream targets, and genetic variants. One CpG island overlaps transcription start site of the HIF1A gene. Out of over 450 missense variants, four have predicted deleterious effect on protein function by at least five bioinformatics tools. Currently there are 85 miRNAs reported to target HIF1A. HIF1A downstream targets include protein-coding genes, long noncoding RNAs, and microRNAs (hypoxamiRs). The study presents the first integration of heterogeneous molecular interactions associated with HIF1A gene enabling a holistic view of the gene and lays the groundwork for supplementing the data in the future. Full article
(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)
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Article
Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth
Genes 2021, 12(8), 1145; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081145 - 27 Jul 2021
Viewed by 467
Abstract
Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, [...] Read more.
Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ- and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity. Full article
(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)
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Review

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Review
Genetic Background of Congenital Erythrocytosis
Genes 2021, 12(8), 1151; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081151 - 28 Jul 2021
Cited by 1 | Viewed by 451
Abstract
True erythrocytosis is present when the red cell mass is greater than 125% of predicted sex and body mass, which is reflected by elevated hemoglobin and hematocrit. Erythrocytosis can be primary or secondary and congenital or acquired. Congenital defects are often found in [...] Read more.
True erythrocytosis is present when the red cell mass is greater than 125% of predicted sex and body mass, which is reflected by elevated hemoglobin and hematocrit. Erythrocytosis can be primary or secondary and congenital or acquired. Congenital defects are often found in those diagnosed at a young age and with a family history of erythrocytosis. Primary congenital defects mainly include mutations in the Erythropoietin receptor gene but SH2B3 has also been implicated. Secondary congenital erythrocytosis can arise through a variety of genetic mechanisms, including mutations in the genes in the oxygen sensing pathway, with high oxygen affinity hemoglobin variants and mutations in other genes such as BPMG, where ultimately the production of erythropoietin is increased, resulting in erythrocytosis. Recently, mutations in PIEZ01 have been associated with erythrocytosis. In many cases, a genetic variant cannot be identified, leaving a group of patients with the label idiopathic erythrocytosis who should be the subject of future investigations. The clinical course in congenital erythrocytosis is hard to evaluate as these are rare cases. However, some of these patients may well present at a young age and with sometimes catastrophic thromboembolic events. There is little evidence to guide the management of congenital erythrocytosis but the use of venesection and low dose aspirin should be considered. Full article
(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)
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Review
Molecular Pathways Involved in the Development of Congenital Erythrocytosis
Genes 2021, 12(8), 1150; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081150 - 28 Jul 2021
Cited by 1 | Viewed by 367
Abstract
Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains [...] Read more.
Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Review papers:

Title:
Genetic background of Congenital Erythrocytosis
Authors: Mary Frances McMullin

Title: Genetic background of Polycythaemia Vera
Authors: Francois Girodon

Title: Genetic diagnosis of Erythrocytosis
Authors: Celeste Bento

Title: New molecular pathways in Erythrocytosis
Authors: Nataša Debeljak

Research papers:

Title:  HIFA paralogs in cell response to hypoxia
Authors:
Tanja Kunej

Title:  HIF gene atlas
Authors:
Aleša Kristan

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