Key Points
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The inherited disorders of haemoglobin are the commonest genetic diseases.
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These diseases consist of the structural haemoglobin variants, such as sickle-cell haemoglobin, and the thalassaemias, which result in defective globin production.
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The β-thalassaemias are causing an increasingly important public health problem throughout tropical countries.
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The severity and clinical symptoms of the β-thalassaemias are extremely variable.
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Much of the clinical variability of the β-thalassaemias can be accounted for by the complex interactions of the primary thalassaemia mutations, with various secondary and tertiary genetic modifiers and with environmental factors.
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A better understanding of the mechanisms that underlie the phenotypic diversity of this disease offers hope for improved genetic counselling and ways towards new treatment strategies.
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Furthering our understanding of the clinically diverse monogenic disorders should help inform future experimental approaches to unravelling the genetics and pathophysiology of the more common complex diseases.
Abstract
The remarkable phenotypic diversity of the β-thalassaemias reflects the heterogeneity of mutations at the β-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype–genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype–genotype relationships in designing approaches to gene therapy.
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Acknowledgements
This work was supported by the Medical Research Council (MRC) and the Wellcome Trust. I thank my former colleagues in the MRC Molecular Haematology Unit for their help and support.
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ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- THALASSAEMIA
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Inherited disorder caused by the abnormal production of haemoglobin.
- SPLENOMEGALY
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Enlargement of the spleen that results in the pooling of red cells and in anaemia.
- ANAEMIA
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A reduction in the haemoglobin level or red-cell count, which leads to defective tissue oxygenation.
- INTERCURRENT ILLNESS
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An illness unrelated to the primary disease (for example, infection or malnutrition in a child with thalassaemia).
- OSTEOPOROSIS
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Reduction in the amount of bone without a change in its composition. Associated with bone pain and fractures.
- HAEMOLYTIC ANAEMIA
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Anaemia due to reduced red-cell survival.
- ERYTHROPOIESIS
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Differentiation and maturation of red blood cells.
- BILIRUBIN
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A principal metabolic product of haemoglobin breakdown.
- HYPOGONADISM
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Reduction in ovarian or testicular function. This might be primary, due to disease of the ovaries or testes, or secondary due to disease of the hypothalamic–pituitary axis.
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Weatherall, D. Phenotype—genotype relationships in monogenic disease: lessons from the thalassaemias . Nat Rev Genet 2, 245–255 (2001). https://doi.org/10.1038/35066048
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DOI: https://doi.org/10.1038/35066048
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