Genetic Modifiers in Hemoglobinopathies

Hematology Department, Hadassah University Hospital, Ein Kerem, Jerusalem Israel IL91120, Israel.
Current Molecular Medicine (Impact Factor: 3.62). 12/2008; 8(7):600-8. DOI: 10.2174/156652408786241410
Source: PubMed


Hereditary anemias show considerable variation in their clinical presentation. In some cases, the causes of these variations are easily apparent. In thalassemia (or in HbE/thalassemia), genetic variation is primarily caused by the severity of the thalassemia mutation. However, not uncommonly, there is variation unexplained by the globin gene mutations themselves, which may be caused by genetic modifiers. In sickle cell disease, the primary mutation is the same in all patients. Therefore, variations in disease severity generally are due to genetic modifiers. In most genetic diseases involving beta globin, the most clearcut influence on phenotype results from elevated fetal hemoglobin levels. In addition, alpha globin gene number can influence disease phenotype. In thalassemia major or intermedia, reduction in the number of alpha globin genes can ameliorate the disease phenotype; conversely, excess alpha globin genes can convert beta thalassemia trait to a clinical picture of thalassemia intermedia. In sickle cell disease, the number of alpha globin genes has both ameliorating and exacerbating effects, depending on which disease manifestation is being examined. Unlinked genetic factors have substantial effects on the phenotype of hereditary anemias, both on the anemia and other disease manifestations. Recently, studies using genome-wide techniques, particularly studying QTLs causing elevated HbF, or affecting HbE/thalassemia, have revealed other genetic elements whose mechanisms are under study. The elucidation of genetic modifiers will hopefully lead to more rational and effective management of these diseases.

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    • "Both thalassemias and homozygous SCD represent considerable variations in their clinical presentations, especially when inherited together. The clinical and hematological manifestations of sickle cell anemia (SCA) have been found to be altered by the presence of α- and β-thals [13, 14]. Moreover, several studies have shown that the coexistence of α-thal with SCA can produce consequences that are beneficial in some complications but detrimental in others [15]. "
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    ABSTRACT: The frequency of hemoglobinopathies is still high in Adana, the biggest city of the Cukurova Region that is located in the southern part of Turkey. Our aim was to identify the concomitant mutations in α- and β-globin genes which lead to complex hemoglobinopathies and to establish an appropriate plan of action for each subject, particularly when prenatal diagnosis is necessary. We studied the association between the β-globin gene and α-thalassemia genotypes. The reverse hybridization technique was employed to perform molecular analysis, and the results were confirmed by amplification refractory mutation system (ARMS) or restriction fragment length polymorphism (RFLP) technique. We evaluated 36 adult subjects (28 female and 8 male; age range: 18-52 years) with concomitant mutations in their α- and β-globin genes. The -α(3.7)/αα deletion was the commonest defect in the α-chain as expected, followed by α(3.7)/-α(3.7) deletion. Twenty-five of 36 cases were sickle cell trait with coexisting α-thalassemia, while seven Hb S/S patients had concurrent mutations in their α-genes. The coexistence of α(PolyA-2)α/αα with Hb A/D and with Hb S/D, which is very uncommon, was also detected. There was a subject with compound heterozygosity for β-globin chain (-α(3.7)/αα with IVSI.110/S), and also a case who had -α(3.7)/αα deletion with IVSI.110/A. Although limited, our data suggest that it would be valuable to study coexisting α-globin mutations in subjects with sickle cell disease or β-thalassemia trait during the screening programs for premarital couples, especially in populations with a high frequency of hemoglobinopathies.
    Full-text · Article · Sep 2012
    • "The presence of an α thal-2 in which only one of the four α genes is inefficient is one of the most common genetic modifications observed worldwide. An interaction of this situation with other globin abnormalities should always be considered as a possible modulator factor31. In a carrier of a β- thalassaemic trait the co-existence of an α-thalassaemia will partially compensate the disequilibrium in globin synthesis; due to a lesser amount of toxic free α globin chain bound to the red cell membrane, the hypochromic anaemia will be much better tolerated. "
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    ABSTRACT: Haemoglobin (Hb) abnormalities though quite frequent, are generally detected in populations during surveys and programmes run for prevention of Hb disorders. Several methods are now available for detection of Hb abnormalities. In this review, the following are discussed: (i) the methods used for characterization of haemoglobin disorders; (ii) the problems linked to diagnosis of thalassaemic trait; (iii) the strategy for detection of common Hb variants; and (iv) the difficulties in identification of rare variants. The differences between developing and industrialized countries for the strategies employed in the diagnosis of abnormal haemoglobins are considered. We mention the limits and pitfalls for each approach and the necessity to characterize the abnormalities using at least two different methods. The recommended strategy is to use a combination of cation-exchange high performance chromatography (CE-HPLC), capillary electrophoresis (CE) and when possible isoelectric focusing (IEF). Difficult cases may demand further investigations requiring specialized protein and/or molecular biology techniques.
    No preview · Article · Oct 2011 · The Indian Journal of Medical Research
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    • "Anemias can result from insufficient dietary iron uptake but there are also a multitude of other environmental causes (Umbreit 2005). Mutations in genes coding globin polypeptide chains, iron uptake and processing proteins and other proteins required for the synthesis and assembly of hemoglobin and red blood cells are among the many genetic bases for anemias (Rund and Fucharoen 2008; Camaschella 2009; Iolascon et al. 2009). Symptoms of anemias usually consist of a general feeling of weakness and fatigue due to a lack of oxygen delivery to skeletal muscles combined with other symptoms that are indicative of the underlying cause of the disease. "
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    ABSTRACT: Transition metal ions are essential nutrients to all forms of life. Iron, copper, zinc, manganese, cobalt and nickel all have unique chemical and physical properties that make them attractive molecules for use in biological systems. Many of these same properties that allow these metals to provide essential biochemical activities and structural motifs to a multitude of proteins including enzymes and other cellular constituents also lead to a potential for cytotoxicity. Organisms have been required to evolve a number of systems for the efficient uptake, intracellular transport, protein loading and storage of metal ions to ensure that the needs of the cells can be met while minimizing the associated toxic effects. Disruptions in the cellular systems for handling transition metals are observed as a number of diseases ranging from hemochromatosis and anemias to neurodegenerative disorders including Alzheimer's and Parkinson's disease. The yeast Saccharomyces cerevisiae has proved useful as a model organism for the investigation of these processes and many of the genes and biological systems that function in yeast metal homeostasis are conserved throughout eukaryotes to humans. This review focuses on the biological roles of iron, copper, zinc, manganese, nickel and cobalt, the homeostatic mechanisms that function in S. cerevisiae and the human diseases in which these metals have been implicated.
    Full-text · Article · Apr 2011 · Biology of Metals
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