Submit to Genes Review for Genes Propose a Special Issue

Journal Browser

Genetics and Genomics of Erythrocytosis

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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 (30 October 2021) | Viewed by 32088

Share This Special Issue

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
Special Issues, Collections and Topics in MDPI journals

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 submissions that pass pre-check are 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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (10 papers)

Download All Papers

Research

Jump to: Review, Other

6 pages, 236 KiB

Open AccessFeature PaperArticle

Importance of Sequencing HBA1, HBA2 and HBB Genes to Confirm the Diagnosis of High Oxygen Affinity Hemoglobin

by Mathilde Filser, Betty Gardie, Mathieu Wemeau, Patricia Aguilar-Martinez, Muriel Giansily-Blaizot and François Girodon

Genes 2022, 13(1), 132; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13010132 - 12 Jan 2022

Cited by 3 | Viewed by 2255

Abstract

High oxygen affinity hemoglobin (HOAH) is the main cause of constitutional erythrocytosis. Mutations in the genes coding the alpha and beta globin chains (HBA1, HBA2 and HBB) strengthen the binding of oxygen to hemoglobin (Hb), bringing about tissue hypoxia and a secondary erythrocytosis. The diagnosis of HOAH is based upon the identification of a mutation in HBA1, HBA2 or HBB in specialized laboratories. Phenotypic studies of Hb are also useful, but electrophoretic analysis can be normal in 1/3 of cases. The establishment of the dissociation curve of Hb can be used as another screening test, a shift to the left indicating an increased affinity for Hb. The direct measurement of venous P50 using a Hemox Analyzer is of great importance, but due to specific analytic conditions, it is only available in a few specialized laboratories. Alternatively, an estimated measurement of the P50 can be obtained in most of the blood gas analyzers on venous blood. The aim of our study was therefore to determine whether a normal venous P50 value could rule out HOAH. We sequenced the HBB, HBA1 and HBA2 genes of 75 patients with idiopathic erythrocytosis. Patients had previously undergone an exhaustive medical check-up after which the venous P50 value was defined as normal. Surprisingly, sequencing detected HOAH in three patients (Hb Olympia in two patients, and Hb St Nazaire in another). A careful retrospective examination of their medical files revealed that (i) one of the P50 samples was arterial; (ii) there was some air in another sample; and (iii) the P50 measurement was not actually done in one of the patients. Our study shows that in real life conditions, due to pre-analytical contingencies, a venous P50 value that is classified as being normal may not be sufficient to rule out a diagnosis of HOAH. Therefore, we recommend the systematic sequencing of the HBB, HBA1 and HBA2 genes in the exploration of idiopathic erythrocytosis. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

7 pages, 232 KiB

Open AccessArticle

NGS Evaluation of a Bernese Cohort of Unexplained Erythrocytosis Patients

by Katarzyna Aleksandra Jalowiec, Kristina Vrotniakaite-Bajerciene, Annina Capraru, Tatiana Wojtovicova, Raphael Joncourt, Alicia Rovó and Naomi A. Porret

Genes 2021, 12(12), 1951; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12121951 - 04 Dec 2021

Cited by 5 | Viewed by 1944

Abstract

(1) Background: Clinical and molecular data on patients with unexplained erythrocyto-sis is sparse. We aimed to analyze the clinical and molecular features of patients with congenital erythrocytosis in our tertiary reference center. (2) Methods: In 34 patients with unexplained erythrocytosis, a 13-gene Next-Generation Sequencing erythrocytosis panel developed at our center was conducted. (3) Results: In 6/34 (18%) patients, eight different heterozygous gene variants were found. These patients were, therefore, diagnosed with congenital erythrocytosis. Two patients had two different gene variants each. All variants were characterized as variants of unknown significance as they had not previously been described in the literature. The rest of the patients (28/34, 82%) had no detected gene variants. (4) Conclusions: Our experience shows that the NGS panel can be helpful in determining the reasons for persistent, unexplained erythrocytosis. In our cohort of patients with erythrocytosis, we identified some, thus far unknown, gene variants which may explain the clinical picture. However, further investigations are needed to determine the relationship between the molecular findings and the phenotype. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

17 pages, 2270 KiB

Open AccessArticle

Integration and Visualization of Regulatory Elements and Variations of the EPAS1 Gene in Human

by Aleša Kristan, Nataša Debeljak and Tanja Kunej

Genes 2021, 12(11), 1793; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12111793 - 13 Nov 2021

Cited by 7 | Viewed by 2663

Abstract

Endothelial PAS domain-containing protein 1 (EPAS1), also HIF2α, is an alpha subunit of hypoxia-inducible transcription factor (HIF), which mediates cellular and systemic response to hypoxia. EPAS1 has an important role in the transcription of many hypoxia-responsive genes, however, it has been less researched than HIF1α. The aim of this study was to integrate an increasing number of data on EPAS1 into a map of diverse OMICs elements. Publications, databases, and bioinformatics tools were examined, including Ensembl, MethPrimer, STRING, miRTarBase, COSMIC, and LOVD. The EPAS1 expression, stability, and activity are tightly regulated on several OMICs levels to maintain complex oxygen homeostasis. In the integrative EPAS1 map we included: 31 promoter-binding proteins, 13 interacting miRNAs and one lncRNA, and 16 post-translational modifications regulating EPAS1 protein abundance. EPAS1 has been associated with various cancer types and other diseases. The development of neuroendocrine tumors and erythrocytosis was shown to be associated with 11 somatic and 20 germline variants. The integrative map also includes 12 EPAS1 target genes and 27 interacting proteins. The study introduced the first integrative map of diverse genomics, transcriptomics, proteomics, regulomics, and interactomics data associated with EPAS1, to enable a better understanding of EPAS1 activity and regulation and support future research. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

► Show Figures

Figure 1

14 pages, 4082 KiB

Open AccessArticle

Integrative Map of HIF1A Regulatory Elements and Variations

by Tanja Kunej

Genes 2021, 12(10), 1526; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12101526 - 28 Sep 2021

Cited by 13 | Viewed by 2956

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 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)

► Show Figures

Figure 1

16 pages, 3355 KiB

Open AccessArticle

Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth

by Tijana Subotički, Olivera Mitrović Ajtić, Dragoslava Đikić, Juan F. Santibanez, Milica Tošić and Vladan P. Čokić

Genes 2021, 12(8), 1145; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081145 - 27 Jul 2021

Cited by 2 | Viewed by 1901

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, 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)

► Show Figures

Figure 1

Review

Jump to: Research, Other

29 pages, 3809 KiB

Open AccessReview

Genetic Background of Polycythemia Vera

by Mathilde Regimbeau, Romain Mary, François Hermetet and François Girodon

Genes 2022, 13(4), 637; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13040637 - 02 Apr 2022

Cited by 7 | Viewed by 4824

Abstract

Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the V617F mutation detected in nearly 98% of cases. That’s why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

► Show Figures

Figure 1

27 pages, 1785 KiB

Open AccessReview

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

by Petra Hudler and Mojca Urbancic

Genes 2022, 13(2), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13020362 - 17 Feb 2022

Cited by 12 | Viewed by 5744

Abstract

Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. The diverse roles of VHL confirm its implication in several crucial cellular processes. VHL variations have been associated with the development of VHL disease and erythrocytosis. The association between genotypes and phenotypes still remains ambiguous for the majority of mutations. It appears that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Understanding the pathogenic effects of VHL variants might better predict the prognosis and optimize management of the patient. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

► Show Figures

Figure 1

9 pages, 335 KiB

Open AccessReview

Genetic Background of Congenital Erythrocytosis

by Mary Frances McMullin

Genes 2021, 12(8), 1151; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081151 - 28 Jul 2021

Cited by 10 | Viewed by 3963

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 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)

► Show Figures

Figure 1

20 pages, 1870 KiB

Open AccessReview

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

by Jana Tomc and Nataša Debeljak

Genes 2021, 12(8), 1150; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081150 - 28 Jul 2021

Cited by 5 | Viewed by 2828

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 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)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

7 pages, 785 KiB

Open AccessCase Report

Identification of Two Novel EPOR Gene Variants in Primary Familial Polycythemia: Case Report and Literature Review

by Laura Lo Riso, Gardenia Vargas-Parra, Gemma Navarro, Leonor Arenillas, Lierni Fernández-Ibarrondo, Beatriz Robredo, Carmen Ballester, Bernardo López, Albert Perez-Montaña, Antonia Sampol, Lourdes Florensa, Carles Besses, María Antonia Duran and Beatriz Bellosillo

Genes 2022, 13(10), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101686 - 20 Sep 2022

Viewed by 1406

Abstract

Primary familial and congenital polycythemia is a rare disease characterized by an increase in red cell mass that may be due to pathogenic variants in the EPO receptor (EPOR) gene. To date, 33 genetic variants have been reported to be associated. We analyzed the presence of EPOR variants in two patients with polycythemia in whom JAK2 pathogenic variants had been previously discarded. Molecular analysis of the EPOR gene was performed by Sanger sequencing of the coding regions and exon/intron boundaries of exon 8. We performed in vitro culture of erythroid progenitor cells. Segregation studies were done whenever possible. The two patients studied showed hypersensitivity to EPO in in vitro cultures. Analysis of the EPOR gene unveiled two novel pathogenic variants. Genetic testing of asymptomatic relatives could guarantee surveillance and proper management. Full article

(This article belongs to the Special Issue Genetics and Genomics of Erythrocytosis)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Genetics and Genomics of Erythrocytosis

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI