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Genetic Research of Iron Homeostasis and Related Diseases
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Genetic Research of Iron Homeostasis and Related Diseases

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 (25 June 2022) | Viewed by 28345

Special Issue Editor

Prof. Dr. Mayka Sánchez Fernández

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Guest Editor
Departamento de Ciencias Básicas de Ciencias de la Salud, Universitat Internacional de Catalunya, Immaculada, 22, 08127 Barcelona, Spain
Interests: iron metabolism; iron regulation; iron diseases; RNA biology; human genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Iron is an important micronutrient that is most known for being the cornerstone of the hematopoietic process. However, the role of iron expands beyond red blood cells production as it is part of iron containing proteins, in the form of heme groups, Fe/S clusters, or directly as iron-proteins. Therefore, iron is involved in many other vital cellular processes and responses, such as oxidation–reduction reactions, mitochondrial respiratory chain, neurotransmitters production, DNA/RNA synthesis, inflammation, infection, and so on.

In mammals, iron levels are sensed and regulated by the liver-secreted hormone, hepcidin. At a cellular level, iron homeostasis is controlled by IRP1 and IRP2, two iron-sensing proteins that control the expression of the genes involved in iron uptake, storage, and utilization at a post-transcriptional level.

Iron metabolism dysregulation leads to iron-related diseases including different forms of acquired or inherited anaemias, i.e., myelodysplastic syndrome, congenital sideroblastic anemia, congenital dyserythropoietic anemia, atransferrinemia, aceruloplasminemia, IRIDA (iron-refractory iron deficiency anemia), and other types of iron-related anemias; acquired or hereditary iron-overload conditions, such as hereditary hemochromatosis, iron-related neurodegenerative diseases, or ataxias; and diseases involving dysfunctional Fe/S cluster proteins, such as multiple mitochondrial dysfunction syndromes. 

Great efforts have been made to reveale the genetic causes of most of these diseases, as well as their underlying molecular regulatory mechanisms. In the future, we will certainly maintain this progress, uncovering additional novel genes involved in iron-related diseases and advancing in our knowledge concerning iron regulation in health and disease, all of which will significantly contribute to the development of new therapies.

This Special Issue is focused on contributing works including genetic, molecular, bioinformatics, and clinical studies on iron homeostasis, genetic iron regulation, and iron-related diseases. With the help of your contribution, we hope to reach a better understanding of the normal and aberrant regulation of iron homeostasis and its diseases, leading to better diagnostics and treatments for affected patients with these conditions.

 

Prof. Dr. Mayka Sánchez Fernández
Guest Editor

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Keywords

  • Iron homeostasis
  • Gene regulation
  • Gene expression
  • Heme proteins
  • Fe/S cluster
  • Iron metabolism
  • Anemia
  • Iron-overload diseases

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Published Papers (8 papers)

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Research

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8 pages, 2117 KiB  
Article
Common Single Nucleotide Polymorphism of TMPRSS6, an Iron Regulation Gene, Associated with Variable Red Blood Cell Indices in Deletional α-Globin Genotypes
by Thidarat Suksangpleng, Waraporn Glomglao and Vip Viprakasit
Genes 2022, 13(9), 1502; https://doi.org/10.3390/genes13091502 - 23 Aug 2022
Cited by 1 | Viewed by 1886
Abstract
Red blood cell (RBC) indices, including mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH), have been widely used for primary screening for thalassaemia (thal) syndromes. Recently, a single nucleotide polymorphism (SNP) rs855791 of TMPRSS6, an iron regulation gene involved in the [...] Read more.
Red blood cell (RBC) indices, including mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH), have been widely used for primary screening for thalassaemia (thal) syndromes. Recently, a single nucleotide polymorphism (SNP) rs855791 of TMPRSS6, an iron regulation gene involved in the substitution of a nucleotide between thymine (T) and cytosine (C) in exon 17 resulted in an amino acid change, p.Val736Ala (V736A), has been described to associate with RBC indices. The objective was to study the effects of common SNP V736A on RBC indices in deletional α-thal variations. SNP rs855791 genotypes were identified from 433 Thai volunteers, including 32.6% males and 67.4% females with an average age of 23.0 ± 8.7 years. These populations included individuals (82.4%) who had normal globin genotype (αα/αα, ββ) and α-thal carriers, which were divided into two subgroups, including α+-thal (-α/αα) (14.1%) and αo-thal (--/αα) (3.5%). Among three SNP genotypes, the C allele gradually expressed higher MCV and MCH than those of the T allele in both α+- and αo-thal traits. Importantly, SNP rs855791 of TMPRSS6 responded to α-globin deletions for sustaining RBC sizes and haemoglobinisation in α-thal carriers. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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13 pages, 832 KiB  
Article
IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology
by Vera Hoving, Scott E. Korman, Petros Antonopoulos, Albertine E. Donker, Saskia E. M. Schols and Dorine W. Swinkels
Genes 2022, 13(8), 1309; https://doi.org/10.3390/genes13081309 - 23 Jul 2022
Cited by 2 | Viewed by 2396
Abstract
Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The [...] Read more.
Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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8 pages, 687 KiB  
Article
Quality of Life Scores Remained Different among the Genotypic Groups of Patients with Suspected Hemochromatosis, Even after Treatment Period
by Luis Alfredo Utria Acevedo, Aline Morgan Alvarenga, Paula Fernanda Silva Fonseca, Nathália Kozikas da Silva, Rodolfo Delfini Cançado, Flavio Augusto Naoum, Carla Luana Dinardo, Alexandre Costa Pereira, Pierre Brissot and Paulo Caleb Junior Lima Santos
Genes 2022, 13(1), 118; https://doi.org/10.3390/genes13010118 - 10 Jan 2022
Cited by 3 | Viewed by 1678
Abstract
Background: Hemochromatosis is a genetic condition of iron overload caused by deficiency of hepcidin. In a previous stage of this study, patients with suspected hemochromatosis had their quality of life (QL) measured. We observed that QL scores differed among genotypic groups of patients. [...] Read more.
Background: Hemochromatosis is a genetic condition of iron overload caused by deficiency of hepcidin. In a previous stage of this study, patients with suspected hemochromatosis had their quality of life (QL) measured. We observed that QL scores differed among genotypic groups of patients. In this reported final phase of the study, the aims were to compare QL scores after a treatment period of approximately 3 years and to analyze a possible association of the serum ferritin values with QL scores. Methods: Sixty-five patients were enrolled in this final phase and divided into group 1 (patients that showed primary iron overload and homozygous genotype for the HFE p.Cys282Tyr mutation) and group 2 (other kinds of genotypes). Short Form 36 (SF-36) was performed and consisted of eight domains with a physical and also a mental component. Results: Both groups had a significant decrease in serum ferritin concentrations: group 1 had a variation from 1844 ± 1313 ng/mL to 281 ± 294 ng/mL, and group 2 had a variation from 1216 ± 631 ng/mL to 236 ± 174 ng/mL. Group 1 had a smaller mean value for these six SF-36 domains compared with group 2, indicating a worse QL. Conclusions: In this final stage, six domains demonstrated a difference among genotypic groups (role emotional and mental health, adding to the four of the initial phase), reassuring the impact of the identified genotype on the QL of hemochromatosis patients. Furthermore, despite that both patient groups demonstrated similar and significant decreases in serum ferritin values, no association was found between the decrease in this biological parameter and the SF-36 domains. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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25 pages, 7597 KiB  
Article
New Mutations in HFE2 and TFR2 Genes Causing Non HFE-Related Hereditary Hemochromatosis
by Gonzalo Hernández, Xenia Ferrer-Cortès, Veronica Venturi, Melina Musri, Martin Floor Pilquil, Pau Marc Muñoz Torres, Ines Hernandez Rodríguez, Maria Àngels Ruiz Mínguez, Nicholas J. Kelleher, Sara Pelucchi, Alberto Piperno, Esther Plensa Alberca, Georgina Gener Ricós, Eloi Cañamero Giró, Santiago Pérez-Montero, Cristian Tornador, Jordi Villà-Freixa and Mayka Sánchez
Genes 2021, 12(12), 1980; https://doi.org/10.3390/genes12121980 - 13 Dec 2021
Cited by 8 | Viewed by 4072
Abstract
Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of [...] Read more.
Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of hemochromatosis, while non-HFE related hemochromatosis are rare cases. Here, we describe six new patients of non-HFE related HH from five different families. Two families (Family 1 and 2) have novel nonsense mutations in the HFE2 gene have novel nonsense mutations (p.Arg63Ter and Asp36ThrfsTer96). Three families have mutations in the TFR2 gene, one case has one previously unreported mutation (Family A—p.Asp680Tyr) and two cases have known pathogenic mutations (Family B and D—p.Trp781Ter and p.Gln672Ter respectively). Clinical, biochemical, and genetic data are discussed in all these cases. These rare cases of non-HFE related hereditary hemochromatosis highlight the importance of an earlier molecular diagnosis in a specialized center to prevent serious clinical complications. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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19 pages, 1740 KiB  
Article
Iron Deficiency Caused by Intestinal Iron Loss—Novel Candidate Genes for Severe Anemia
by Carolina Huettmann, Matthias Stelljes, Sugirthan Sivalingam, Manfred Fobker, Alexis Vrachimis, Anne Exler, Christian Wenning, Carola Wempe, Matthias Penke, Andreas Buness, Kerstin U. Ludwig, Martina U. Muckenthaler and Andrea U. Steinbicker
Genes 2021, 12(12), 1869; https://doi.org/10.3390/genes12121869 - 24 Nov 2021
Cited by 2 | Viewed by 3223
Abstract
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below [...] Read more.
The adult human body contains about 4 g of iron. About 1–2 mg of iron is absorbed every day, and in healthy individuals, the same amount is excreted. We describe a patient who presents with severe iron deficiency anemia with hemoglobin levels below 6 g/dL and ferritin levels below 30 ng/mL. Although red blood cell concentrates and intravenous iron have been substituted every month for years, body iron stores remain depleted. Diagnostics have included several esophago-gastro-duodenoscopies, colonoscopies, MRI of the liver, repetitive bone marrow biopsies, psychological analysis, application of radioactive iron to determine intact erythropoiesis, and measurement of iron excretion in urine and feces. Typically, gastrointestinal bleeding is a major cause of iron loss. Surprisingly, intestinal iron excretion in stool in the patient was repetitively increased, without gastrointestinal bleeding. Furthermore, whole exome sequencing was performed in the patient and additional family members to identify potential causative genetic variants that may cause intestinal iron loss. Under different inheritance models, several rare mutations were identified, two of which (in CISD1 and KRI1) are likely to be functionally relevant. Intestinal iron loss in the current form has not yet been described and is, with high probability, the cause of the severe iron deficiency anemia in this patient. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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13 pages, 475 KiB  
Article
Identification of Novel Mutations by Targeted NGS Panel in Patients with Hyperferritinemia
by Giulia Ravasi, Sara Pelucchi, Francesca Bertola, Martina Maria Capelletti, Raffaella Mariani and Alberto Piperno
Genes 2021, 12(11), 1778; https://doi.org/10.3390/genes12111778 - 9 Nov 2021
Cited by 5 | Viewed by 2367
Abstract
Background. Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next [...] Read more.
Background. Several inherited diseases cause hyperferritinemia with or without iron overload. Differential diagnosis is complex and requires an extensive work-up. Currently, a clinical-guided approach to genetic tests is performed based on gene-by-gene sequencing. Although reasonable, this approach is expensive and time-consuming and Next Generation Sequencing (NGS) technology may provide cheaper and quicker large-scale DNA sequencing. Methods. We analysed 36 patients with non-HFE-related hyperferritinemia. Liver iron concentration was measured in 33 by magnetic resonance. A panel of 25 iron related genes was designed using SureDesign software. Custom libraries were generated and then sequenced using Ion Torrent PGM. Results. We identified six novel mutations in SLC40A1, three novel and one known mutation in TFR2, one known mutation and a de-novo deletion in HJV, and a novel mutation in HAMP in ten patients. In silico analyses supported the pathogenic role of the mutations. Conclusions. Our results support the use of an NGS-based panel in selected patients with hyperferritinemia in a tertiary center for iron metabolism disorders. However, 26 out of 36 patients did not show genetic variants that can individually explain hyperferritinemia and/or iron overload suggesting the existence of other genetic defects or gene-gene and gene-environment interactions needing further studies. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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Review

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26 pages, 1839 KiB  
Review
Causes and Pathophysiology of Acquired Sideroblastic Anemia
by Juan Jose Rodriguez-Sevilla, Xavier Calvo and Leonor Arenillas
Genes 2022, 13(9), 1562; https://doi.org/10.3390/genes13091562 - 30 Aug 2022
Cited by 8 | Viewed by 7962
Abstract
The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear [...] Read more.
The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear ring of green-blue granules. The mechanisms that lead to the ring sideroblast formation are heterogeneous, but in all of them, there is an abnormal deposition of iron in the mitochondria of erythroblasts. Congenital sideroblastic anemias include nonsyndromic and syndromic disorders. Acquired sideroblastic anemias include conditions that range from clonal disorders (myeloid neoplasms as myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with ring sideroblasts) to toxic or metabolic reversible sideroblastic anemia. In the last 30 years, due to the advances in genomic techniques, a deep knowledge of the pathophysiological mechanisms has been accomplished and the bases for possible targeted treatments have been established. The distinction between the different forms of sideroblastic anemia is based on the study of the characteristics of the anemia, age of diagnosis, clinical manifestations, and the performance of laboratory analysis involving genetic testing in many cases. This review focuses on the differential diagnosis of acquired disorders associated with ring sideroblasts. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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11 pages, 1110 KiB  
Review
Conservation in the Iron Responsive Element Family
by Karl Volz
Genes 2021, 12(9), 1365; https://doi.org/10.3390/genes12091365 - 30 Aug 2021
Cited by 10 | Viewed by 3662
Abstract
Iron responsive elements (IREs) are mRNA stem-loop targets for translational control by the two iron regulatory proteins IRP1 and IRP2. They are found in the untranslated regions (UTRs) of genes that code for proteins involved in iron metabolism. There are ten “classic” IRE [...] Read more.
Iron responsive elements (IREs) are mRNA stem-loop targets for translational control by the two iron regulatory proteins IRP1 and IRP2. They are found in the untranslated regions (UTRs) of genes that code for proteins involved in iron metabolism. There are ten “classic” IRE types that define the conserved secondary and tertiary structure elements necessary for proper IRP binding, and there are 83 published “IRE-like” sequences, most of which depart from the established IRE model. Here are structurally-guided discussions regarding the essential features of an IRE and what is important for IRE family membership. Full article
(This article belongs to the Special Issue Genetic Research of Iron Homeostasis and Related Diseases)
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