The thalassemias are a heterogeneous group of inherited disorders characterized by a microcytic, hypochromic anemia and an imbalance in the synthesis of the globin chains. Depending on the type(s) of affected chain different forms are recognized: beta-thal, delta-thal, gamma-thal, deltabeta-thal, Agammadeltabeta-thal, epsilongammadeltabeta-thal, and alpha-thal. For instance, in beta-thal trait the beta/alpha in vitro synthetic ratio is usually decreased from the normal value of ~1.00 to 0.5-0.8, while in alpha-thal this ratio is above 1 (1.2-1.6). The beta/alpha ratios in the deltabeta-thal trait conditions are comparable to those seen in beta-thal heterozygotes. Both alpha- and beta-thal are common disorders and are found at high frequencies in populations of countries where malaria is (or was) endemic; beta-thal, for instance, is prevalent in Southeast Asia and Southern China, India, Middle Eastern countries, North African and other Mediterranean countries. Although the first report describing a thalassemic condition appeared in 1925 (1,2) its astonishing heterogeneity was recognized only some 20 years ago when fast, advanced protein analytical methods, and later, molecular biological procedures were applied. Besides the named types of beta-thal, closely related conditions such as the deletional and nondeletional hereditary persistence of fetal hemoglobin (HPFH), were discovered; no distinct changes in the beta/alpha [or (beta+gamma)/alpha] ratio are present and anemia, microcytosis, and hypochromia are absent. These conditions are likewise caused by (large) deletions involving the delta- and beta-globin genes, while the nondeletional HPFH results from mutations in the promoter regions of the gamma-globin genes.

In order to understand the numerous thalassemic conditions it will be necessary to have a clear understanding of the normal globin gene arrangements. The beta-like globin genes are located on the short arm of chromosome #11; the cluster is arranged in the following order: 5'-epsilon-Ggamma-Agamma-psibeta-delta-beta-3'. There are five active genes: epsilon, the duplicated gamma genes (Ggamma; Agamma), the delta and the beta genes, and one pseudo gene. The activities of the genes during ontogeny follow their arrangement on the chromosome; thus: the epsilon-globin gene is active during the first few months after conception followed by the two gamma-globin genes, while the delta- and beta-globin genes produce >99% of the non-alpha chains in adult life. Each of the genes consists of a 5' promoter segment, a short untranslated region (UTR), initiation codon, exon 1, intron 1 or IVS-I, exon 2, intron 2 or IVS-II, exon 3, terminating codon, an UTR (3'UTR), and a poly A signal (AATAAA). A beta-mRNA starts at the Cap site which is 50 nucleotides (nts) from the initiation codon and consists of the three exons, the 3'UTR, and ends past the poly A site where the poly A tail is attached; thus, the IVS-I and IVS-II sequences are excised by a mechanism known as splicing.

The alpha-like globin genes are arranged in a cluster at the tip of chromosome #16. It consists of an embryonic gene (zeta), two alpha genes (alpha2, alpha1), a gene of undetermined function (theta1), and three pseudo genes (psizeta, psialpha2, psialpha1). The arrangement is: telomere, zeta, psizeta, psialpha2, psialpha1, alpha2, alpha1, theta1, centromere. Each of the three active genes (zeta, the duplicated alpha genes) have a general structure similar to the beta-globin gene: promoter region, 5'UTR, initiation codon, exon 1, IVS-I, exon 2, IVS-II, exon 3, terminating codon, 3'UTR, and poly A signal (AATAAA). The three exons of the two alpha-globin genes have identical sequences; differences have been observed in the second IVS and the 3' UTR.

Although both beta- and alpha-thalassemias are highly heterogeneous, survey data have shown that perhaps only some 20 different beta-thal determinants, and less than 10 alpha-thal determinants, occur at high frequencies in certain populations and are considered to be a serious health problem, particularly in developing countries. Prevention is through education and prenatal diagnosis and treatment by conventional care, blood transfusion, bone marrow transplantation, and perhaps in the future, gene therapy.

This compedium of the more than 300 thalassemia alleles and HPFH determinants will follow this outline:

  1. The Beta-Thal Alleles;
    1. Beta-thal alleles due to mutations or frameshifts;
    2. Beta-thal alleles characterized by deletion of 25 nts and more;
    3. Beta-thal due to insertion of a retrotransposable element;
    4. Frequency data for beta-thal alleles;
    5. Beta-thal unlinked to a beta-globin gene mutation or deletion.

  2. Delta-Thal Alleles.

  3. Gamma-Thal Allele.

  4. The HPFH Alleles;
    1. Nondeletional HPFH;
    2. The so-called Swiss-HPFH which includes the -158 Ggamma and -161 Agamma mutations, gamma-globin gene rearrangements, etc;
    3. The deletional HPFH alleles including Hb Kenya.

  5. The (DeltaBeta)°-Thal Alleles;
    1. The GgammaAgamma(deltabeta)°-thal alleles;
    2. The Lepore hemoglobins;
    3. The Ggamma(Agammadeltabeta)°-thal alleles;
    4. The (epsilongammadeltabeta)°-thal alleles.

  6. The Alpha-Thal Alleles;
    1. The nondeletional alpha-thal alleles;
    2. The deletional alpha-thal alleles (alpha-thal-2);
    3. Alpha-globin gene mutants occurring on a chromosome with a -alpha(3.7 kb) or -alpha(4.2 kb) deletion;
    4. The deletional alpha-thal alleles involving both alpha-globin genes (alpha-thal-1);
    5. The alpha-thal alleles with intact alpha2- and alpha1-globin genes;
    6. Hb H disease.

  7. Register.

1. Cooley, T.B. and Lee, P.: Trans. Am. Pediatr. Soc., 37:29, 1925.
2. Zuelzer, W.W.: J. Pediatr., 49:642, 1956.
3. Weatherall, D.J. and Clegg, J.B.: The Thalassaemia Syndromes, 3rd Edition, Blackwell Scientific Publications, Oxford, 1981.
4. Higgs, D.R. and Weatherall, D.J., editors: The Haemoglobinopathies, Bailliere's Clinical Haematology, Vol. 6, W.B. Saunders Company, London, 1993.

This material is from the book A Syllabus of Thalassemia Mutations (1997) by Titus H.J. Huisman, Marianne F.H. Carver, and Erol Baysal, published by The Sickle Cell Anemia Foundation in Augusta, GA, USA. Copyright © 1997 by Titus H.J. Huisman. All rights reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, microfilming and recording, or by any information storage and retrieval systems, without permission in writing from the Author.