The Molecular Basis of β-Thalassemia
01 May 2013-Cold Spring Harbor Perspectives in Medicine (Cold Spring Harbor Laboratory Press)-Vol. 3, Iss: 5
TL;DR: The β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects, which has provided a paradigm for understanding of much of human genetics.
Abstract: The β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural β gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most β-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of β-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of β-thalassemia has provided a paradigm for understanding of much of human genetics.
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TL;DR: Clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations.
Abstract: Iron deficiency anemia arises when the balance of iron intake, iron stores, and the body's loss of iron are insufficient to fully support production of erythrocytes. Iron deficiency anemia rarely causes death, but the impact on human health is significant. In the developed world, this disease is easily identified and treated, but frequently overlooked by physicians. In contrast, it is a health problem that affects major portions of the population in underdeveloped countries. Overall, the prevention and successful treatment for iron deficiency anemia remains woefully insufficient worldwide, especially among underprivileged women and children. Here, clinical and laboratory features of the disease are discussed, and then focus is placed on relevant economic, environmental, infectious, and genetic factors that converge among global populations.
382 citations
Cites background from "The Molecular Basis of β-Thalassemi..."
...…named thalassemia (see Fucharoen and Weatherall 2012; Gibbons 2012; Musallam et al. 2012; Nienhuis and Nathan 2012; Cao and Kan 2013; Higgs 2013; Thein 2013; Vichinsky 2013) has a more direct relationship with iron deficiency anemia, because both diseases are concentrated within malaria and…...
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TL;DR: The wide spectrum of β-thalassemia mutations could well be explained by looking at its geographical distribution, the history of malaria, wars, invasions, mass migrations, consanguinity and settlements.
Abstract: Background: Haemoglobinopathies constitute the commonest recessive monogenic disorders worldwide, and the treatment of affected individuals presents a substantial global disease burden. β -thalassaemia is characterised by the reduced synthesis (β +) or absence (β o) of the β-globin chains in the HbA molecule, resulting in accumulation of excess unbound α-globin chains that precipitate in erythroid precursors in the bone marrow and in the mature erythrocytes, leading to ineffective erythropoiesis and peripheral haemolysis. Approximately 1.5% of the global population are heterozygotes (carriers) of the β-thalassemias: there is a high incidence in populations extending from the Mediterranean basin throughout the Middle East, the Indian subcontinent, Southeast Asia, Melanesia and into the Pacific IslandsAim: The principal aim of this paper is to review, from a historical standpoint, our knowledge about an ancient disease, the β-thalassemias, and in particular, when, how and in what way β-thalassemia spread worldwide to reach such high incidences in certain populations. Results: Mutations involving the s-globin gene are the most common cause of genetic disorders in humans. To date, more than 350 β -thalassaemia mutations have been reported. Considering the current distribution of β- thalassemia, the wide diversity of mutations and the small number of individual population’s specific mutations, it seems unlikely that β-thalassemia originated in a single place and time. Conclusions: Various processes are known to determine the frequency of genetic disease in human populations. However, it is almost impossible to decide to what extent each process is responsible for the presence of a particular genetic disease. The wide spectrum of β-thalassemia mutations could well be explained by looking at its geographical distribution, the history of malaria, wars, invasions, mass migrations, consanguinity and settlements. The analysis of the molecular spectrum and distribution of haemoglobinopathies allows for the development and improvement of diagnostic tests and management for these disorders.
184 citations
TL;DR: IthaGenes is a new interactive database of haemoglobin variations, which stores information about genes and variations affecting ha Hemoglobin disorders, while embedding the NCBI Sequence Viewer for graphical representation of each variation.
Abstract: Inherited haemoglobinopathies are the most common monogenic diseases, with millions of carriers and patients worldwide. At present, we know several hundred disease-causing mutations on the globin gene clusters, in addition to numerous clinically important trans-acting disease modifiers encoded elsewhere and a multitude of polymorphisms with relevance for advanced diagnostic approaches. Moreover, new disease-linked variations are discovered every year that are not included in traditional and often functionally limited locus-specific databases. This paper presents IthaGenes, a new interactive database of haemoglobin variations, which stores information about genes and variations affecting haemoglobin disorders. In addition, IthaGenes organises phenotype, relevant publications and external links, while embedding the NCBI Sequence Viewer for graphical representation of each variation. Finally, IthaGenes is integrated with the companion tool IthaMaps for the display of corresponding epidemiological data on distribution maps. IthaGenes is incorporated in the ITHANET community portal and is free and publicly available at http://www.ithanet.eu/db/ithagenes.
151 citations
TL;DR: This review focuses on advances in therapies targeting splicing, and highlights the animal models developed to recapitulate disease phenotypes as a model for testing these therapies.
134 citations
TL;DR: Identification of the genetic variants modifying fetal hemoglobin (HbF) production in combination with α globin genotype provide some prediction of disease severity for β thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered.
Abstract: The remarkable phenotypic diversity of β thalassemia that range from severe anemia and transfusion-dependency, to a clinically asymptomatic state exemplifies how a spectrum of disease severity can be generated in single gene disorders. While the genetic basis for β thalassemia, and how severity of the anemia could be modified at different levels of its pathophysiology have been well documented, therapy remains largely supportive with bone marrow transplant being the only cure. Identification of the genetic variants modifying fetal hemoglobin (HbF) production in combination with α globin genotype provide some prediction of disease severity for β thalassemia but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered. Nonetheless, genetic studies have been successful in characterizing the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation. BCL11A has been established as a quantitative repressor, and progress has been made in manipulating its expression using genomic and gene-editing approaches for therapeutic benefits. Recent discoveries and understanding in the mechanisms associated with ineffective and abnormal erythropoiesis have also provided additional therapeutic targets, a couple of which are currently being tested in clinical trials.
128 citations
Cites background from "The Molecular Basis of β-Thalassemi..."
...7 kb) remove the 3′ end of the gene but leave the 5′ end intact [3]....
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...Certain β thalassemia mutations, notably those that involve small deletions or mutations of the promoter sequence of the HBB gene, are associated with much higher levels of HbF production than mutations affecting other regions of HBB (see deletions causing beta thalassemia) [3]....
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...β thalassemia is caused by a spectrum of mutations that results in a quantitative reduction of β globin chains that are structurally normal [3], in contrast to SCD which is caused by an abnormal Hb variant (HbS, βGlu6Val) that results from a point mutation in the HBB gene [4,5]....
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...These are generally mild β thalassemia alleles [3]....
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References
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TL;DR: The results indicate that the DNA regions flanking the human beta-globin locus contain dominant regulatory sequences that specify position-independent expression and normally activate the complete human multigene beta- globin loci.
1,799 citations
TL;DR: This paper aims to explore the role of language and time in the development of romantic attachment and its role in the story of Henry IV.
1,080 citations
Book•
01 Jul 1984
TL;DR: Find the secret to improve the quality of life by reading this hemoglobin molecular genetic and clinical aspects and make the words as your good value to your life.
Abstract: Find the secret to improve the quality of life by reading this hemoglobin molecular genetic and clinical aspects. This is a kind of book that you need now. Besides, it can be your favorite book to read after having this book. Do you ask why? Well, this is a book that has different characteristic with others. You may not need to know who the author is, how well-known the work is. As wise word, never judge the words from who speaks, but make the words as your good value to your life.
912 citations
TL;DR: Together analysis of DNA polymorphisms in the human β-globin gene cluster and in cloned β-genes has revealed the association of specific β-thalassaemia mutations and β-gene polymorphisms with particular flanking polymorphisms.
Abstract: Combined analysis of DNA polymorphisms in the human β-globin gene cluster and in cloned β-genes has revealed the association of specific β-thalassaemia mutations and β-gene polymorphisms with particular flanking polymorphisms. A systematic study of cloned genes identified several new mutations, one of which possibly affects transcription. The strategy used may be applicable to other diseases of single-copy genes.
823 citations
Book•
01 Jan 1972
TL;DR: This work focuses on the treatment and management of thalassaemia withmental retardation or Myelodysplasia, and the many and Diverse Routes to the authors' Current Understanding of the ThalassAemia Syndromes.
Abstract: Authors and Contributors. Preface to the Fourth Edition. Preface to the First Edition. Acknowledgements. Part 1 Historical Background.1. Historical Perspectives: The Many and Diverse Routes to our Current Understanding of the Thalassaemia Syndromes. Part 2 The Biology of The Thalassaemias. 2. Human Haemoglobin 3. Thalassaemia: Classification and Relationship to Other Inherited Diseases of Haemoglobin.4. The Molecular Pathology of the Thalassaemias. 5. Pathophysiology of the Thalassaemias. 6. The World Distribution and Population Genetics of Thalassaemia. Part 3 Clinical Features of the Thalassaemias 7. The beta Thalassaemias.8. The delta beta and Related Thalassaemias 9. The beta and delta beta Thalassaemia in Association with Structural Haemoglobin Variants.10. Hereditary Persistence of Fetal Haemoglobin.11. The alpha Thalassaemias and Their Interactions with Structural Haemoglobin Variants. 12. Thalassaemia withmental retardation or Myelodysplasia. 13. Thalassaemia Intermedia. Part 4 Diagnosis and management of thalassaemia. 14. Avoidance and Population Control.15. Management and prognosis.16. Laboratory Diagnosis of the Thalassaemias. Part 5 The Future. References. Appendix. Index.
791 citations