The Molecular Basis of  -Thalassemia

Thein, Swee Lay

doi:10.1101/cshperspect.a011700

Cited by 291 publications

(215 citation statements)

References 106 publications

(88 reference statements)

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“…The thalassemias are heterogeneous at the molecular level, with more than 200 disease-causing mutations having been identified (Weatherall 2001;Rund and Rachmilewitz 2005;Cao and Galanello 2010;Thein 2013). Alleles characterized by a mild phenotype typically include promoter mutations, although splicing and frameshift mutations have also been discovered in individuals homozygous for b-thalassemia but having a mild phenotype.…”

Section: Genetic Modifiersmentioning

confidence: 99%

Pathophysiology and Clinical Manifestations of the -Thalassemias

Nienhuis

Nathan

2012

Cold Spring Harbor Perspectives in Medicine

149

111

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The b-thalassemia syndromes reflect deficient or absent b-globin synthesis usually owing to a mutation in the b-globin locus. The relative excess of a-globin results in the formation of insoluble aggregates leading to ineffective erythropoiesis and shortened red cell survival. A relatively high capacity for fetal hemoglobin synthesis is a major genetic modifier of disease severity, with polymorphisms in other genes also having a significant role. Iron overload secondary to enhanced absorption and red cell transfusions causes an increase in liver iron and in various other tissues, leading to endocrine and cardiac dysfunction. Modern chelation regimens are effective in removing iron and preserving or restoring organ function.

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Section: Genetic Modifiersmentioning

confidence: 99%

Pathophysiology and Clinical Manifestations of the -Thalassemias

Nienhuis

Nathan

2012

Cold Spring Harbor Perspectives in Medicine

149

111

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“…The molecular basis for the different forms of a and b thalassemia, which are coinherited with HbE, are described by Thein (2012) and Higgs (2012).…”

Section: The Interactions Of Hemoglobin E With Different Forms Of Thamentioning

confidence: 99%

The Hemoglobin E Thalassemias

Fucharoen¹,

Weatherall²

2012

Cold Spring Harbor Perspectives in Medicine

176

114

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Hemoglobin E (HbE) is an extremely common structural hemoglobin variant that occurs at high frequencies throughout many Asian countries. It is a b-hemoglobin variant, which is produced at a slightly reduced rate and hence has the phenotype of a mild form of b thalassemia. Its interactions with different forms of a thalassemia result in a wide variety of clinical disorders, whereas its coinheritance with b thalassemia, a condition called hemoglobin E b thalassemia, is by far the most common severe form of b thalassemia in Asia and, globally, comprises approximately 50% of the clinically severe b-thalassemia disorders.

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“…All these mutations are associated with resistance to malaria; hence, they remain in the gene pool. Thalassemias are inherited diseases arising from gene mutations that affect the mRNA stability or splice, resulting in minimized amounts of a-or b-globin production (185) (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

Hirsch

Sibmooh

Fucharoen

et al. 2017

Antioxidants & Redox Signaling

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Significance: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The b E -globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected. Critical Issues: While HbE by itself presents as a mild anemia and a single gene for b-thalassemia is not serious, it remains unexplained why HbE/b-thalassemia (HbE/b-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/b-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess a-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events. Future Directions: Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26,[794][795][796][797][798][799][800][801][802][803][804][805][806][807][808][809][810][811][812][813]

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The Molecular Basis of -Thalassemia

Cited by 291 publications

References 106 publications

Pathophysiology and Clinical Manifestations of the -Thalassemias

Pathophysiology and Clinical Manifestations of the -Thalassemias

The Hemoglobin E Thalassemias

HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics

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