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Molecular genetics of the thalassemic syndromes

Edward J Benz, Jr, MD
Section Editor
Stanley L Schrier, MD
Deputy Editor
Jennifer S Tirnauer, MD


The deficiencies in hemoglobin biosynthesis that characterize the various forms of thalassemia arise from mutations in or near the two globin gene clusters which encode the globin polypeptide subunits of hemoglobin. To date, no forms of thalassemia arising primarily from defects in iron or heme metabolism have been described. All known forms are due to inherited defects in the biosynthesis or post-translational stability of the globin subunits themselves.

Because of their small size, their arrangement into relatively compact gene clusters, and their well characterized physiology, pathology, and clinical genetics, the globin genes were the first human genes to be cloned and thoroughly characterized. The mutations that cause the thalassemia syndromes were the first to be defined at the level of their DNA structure. Indeed, the delineation of the impact of these mutations on mRNA and protein expression provided the paradigm for the identification of mutations causing other diseases.

The molecular pathology of the thalassemic syndromes will be discussed here. This subject is best understood from the perspective of the normal structure and function of the genes encoding the individual globins [1]. The first section of this review will outline the essential features of normal hemoglobin biosynthesis and its underlying molecular biology. (See "Principles of molecular genetics" and "Structure and function of normal hemoglobins".)

The second section will discuss illustrative examples of the over 100 different mutations causing thalassemia and explain their effects on globin synthesis. The pathophysiologic and clinical aspects of the thalassemic syndromes are discussed separately. (See "Pathophysiology of alpha thalassemia" and "Pathophysiology of beta thalassemia" and "Clinical manifestations and diagnosis of the thalassemias".)


The globin gene clusters and their RNA and globin protein products are the most thoroughly understood in the human genome at the level of their basic structure and arrangement; regulated expression during embryonic, fetal, and adult life; structure-function relationships of the globin proteins; and physiology and pathophysiology of conditions arising from alterations in the genes or elements that control them.

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Literature review current through: Nov 2017. | This topic last updated: Oct 23, 2017.
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