I-a.   Beta-Thalassemia; Nondeletional Mutants

As many as 179 nondeletional beta-thal alleles are described on pages 13 through 138; they are listed from 5' to 3' according to the locations of the nucleotide changes. Each description provides the mutation, type of beta-thal, mechanism, methods used for identification, hematological data, interaction with other beta-thal alleles or with beta chain abnormal hemoglobins (Hbs), incidence, and appropriate references. Occasionally, the information is rather limited, primarily because the allele was reported in an abstract or by personal communication. The alleles are due to single nucleotide (nt) changes and frameshifts resulting in small or somewhat larger deletions (up to 17 bp) or extensions. Some rather complex rearrangements have also been reported for a few rare determinants. The alleles can be divided into subgroups according to the types of changes, and this information is provided in Table I. The reader is also invited to consult the sequence of the beta-globin gene which is listed in Figure 1 and Figure 2 [Not yet available].

[Figure not yet available.]

FIG. 1. Mutations and deletions in the promoter and 5'UTR regions of the beta-globin gene leading to a mild beta-thal. Positions of four conserved segments of nts are underlined: the CACCC boxes at -105 through -101 and at -90 through -86; the CCAAT box at -76 through -72, and the ATAAAA box at -31 through -26.

The Dominant Types of Beta-Thalassemia

These types result in a thalassemia intermedia in persons carrying one affected beta-globin gene and one normal beta-globin gene. The phenotype shows a mild-to-moderate anemia with inclusion bodies (which greatly increase in number after splenectomy), elevated levels of Hb A2 and Hb F, an imbalance in in vitro chain synthesis, splenomegaly, gross abnormalities of the red cells, nucleated red cells and inclusion bodies in the bone marrow. This rather specific form of beta-thal was first observed in an English family (1) and in a Swiss family (2) during the early 1970s and was named Heinz body or inclusion body beta-thalassemia. The anomaly in both families was later identified as the G->T mutation at codon 121 (3,4).

Hematological and clinical observations made in several families with comparable forms of beta-thal and with certain, often highly unstable Hbs have indicated a striking overlap; many subjects with a detectable unstable Hb variant, and with a dominant type of beta-thal without a detectable abnormal Hb have similar phenotypes. Thein (5,6) has divided the different types of dominant beta-thal into different groups and a similar approach will be followed here.

1.   Hyperunstable Hb Variants

As many as nine different abnormalities have been discovered; all are severely unstable and most often difficult to detect, if at all. The best result is by reversed phase high performance liquid chromatography (HPLC), particularly when lysates from labeled red cells are analyzed. Only a few have been identified by protein analysis; for most, the data are based on results obtained by sequencing the amplified beta-globin gene with confirmation of the mutation by allele specific amplification (ASA) or dot-blot analysis with mutation specific probes.

Mutation Amino acid
Name of variant Observed in:
Codon 28, CTG->CGG Leu->Arg Chesterfield English
Codon 32, CTG->CAG;
Codon 98, GTG->ATG
Medicine Lake Caucasian
Codon 60, GTG->GAG Val->Glu Cagliari Sardinian
Codon 110, CTG->CCG Leu->Pro Showa-Yakushiji Japanese
Codon 114, CTG->CCG Leu->Pro Durham-N.C.; Brescia Caucasians; Italians
Codon 115, GCC->GAC Ala->Asp Hradec Kralove Czech
Codon 126, GTG->GGG Val->Gly Neapolis; Dhonburi Italians; Germans
Codon 127, CAG->CCG Gln->Pro Houston Caucasians
Codon 127, CAG->CGG Gln->Arg Dieppe French

2.   Early Termination of Translation

These six alleles result from point mutations in a specific codon, changing it to a nonsense codon or from a frameshift leading to an early stop codon. The result is a shortened beta chain of 142 residues or less; these chains could carry a heme group because the change in the reading frame occurs beyond the codons providing the amino acids of the helices F and G where the heme moiety is located. However, these truncated beta chains will be unable to combine with alpha chains to form an (abnormal) Hb molecule; instead, the abnormal beta chain will be metabolized by proteolytic enzymes in red cell precursors. Alpha chain aggregates can often be observed in bone marrow cells.

Mutation Length of betaX Name, if any Observed in:
Codons 108-112, -12 bp 142 - Swedish
Codons 120/121, +A 139 - Filipinos
Codon 121, GAA->TAA 120 - Greeks; Swiss; English; Czech; Japanese
Codons 123-125, -ACCCCACC 135 Khon Kaen Thai
Codons 126-131, -17 bp 132 - Pakistani
Codon 127, CAG->TAG 126 - English

3.   Frameshifts Resulting in Extended Beta Chains

These seven nt changes occur exclusively in the third exon and the abnormal transcript has a stop codon 3' to the terminating codon 147 of the normal beta-mRNA. As a result extended beta chains are formed, 156-158 amino acids long, because in most instances the same new stop codon is used. The abnormal beta chain is not detectable and likely is again readily metabolized, resulting in an accumulation of (aggregated) alpha chains.

Mutation Length of betaX Name, if any Observed in:
Codon 94, +TG 158 Agnana Italians
Codon 100, CCT->TCTGAGAACTT 158 - South Africans
Codon 109, -G 156 Manhattan Lithuanians
Codon 123, -A 156 Makabe Japanese
Codon 124, -A 156 - Russians
Codon 125, -A 156 - Japanese
Codon 126, -T 156 Vercelli Italians

4.   Deletions or Additions of One Entire Codon

The deletion of one codon, or three nts from two codons, or the addition of one codon, sometimes resulting in the introduction of a (new) amino acid in the place of two will cause the synthesis of a beta chain which is 145 or 147 amino acids long. A tetrameric Hb molecule can be formed and small amounts of some of these abnormal Hbs (alpha2beta2X) have been isolated. They are, however, unstable and, thus, a similar phenotype is observed as for the variants of the preceeding categories.

Mutation Length of beta+ New amino acid Deleted amino acid Name, if any Observed in:
Codons 24/25, -GGT 145 - Gly - Japanese
Codons 31/32, +CGG 147 Arg - - Spanish
Codons 33/34, -GTG 145 - Val Korea Koreans
Codons 124/126, +CCA 147 Pro - - Russians
Codons 127/128, -AGG 145 Pro Gln·Ala Gunma Japanese

5.   Complex Rearrangements

Three beta-thal alleles have been discovered (all in single families, and as de novo mutations) which have complex changes in the sequence of the beta-globin gene, leading either to the production of an abnormal and unstable beta chain or to no beta chain at all. Some of these patients have a rather severe form of this dominant beta-thal.

Mutation Length of betaX Name, if any Observed in:
Codon 114, -CT; +G 156 Geneva Swiss
Codons 128/129, -4; +5/codons 132-137, -11 153 - Irish
Codons 134-137, -11; +5 144 - Portuguese

Clinically, the phenotypes of all the listed alleles can be quite different and may vary from the classical beta-thal (albeit with a distinct splenomegaly) to a congenital hemolytic anemia with transfusion dependency and marked reticulocytosis. The conditions should not be confused with that seen in a patient with a classical beta-thal heterozygosity [for instance, the codon 39 (C->T) or IVS-I-110 (G->A) mutations] who also carries an alpha-globin gene triplication (alphaalpha/alphaalphaalpha or alphaalphaalpha/alphaalphaalpha); the excessive production of alpha chains together with the decrease in beta chain synthesis will lead to a thalassemia intermedia which is clinically identifiable.

1. Weatherall, D.J., Clegg, J.B., Knox-Macauley, H.H.M., Bunch, C., Hopkins, C.R., and Temperley, I.J.: Br. J. Haematol., 24:681, 1973.
2. Stamatoyannopoulos, G., Woodson, R., Papayannopoulou, Th., Heywood, D., and Kurachi, S.: N. Engl. J. Med., 290:939, 1974.
3. Fei, Y.J., Stoming, T.A., Kutlar, A., Huisman, T.H.J., and Stamatoyannopoulos, G.: Blood, 73:1075, 1989.
4. Thein, S.L., Hesketh, C., Taylor, P., Temperley, I.J., Hutchinson, R.M., Old, J.M., Wood, W.G., Clegg, J.B., and Weatherall, D.J.: Proc. Natl. Acad. Sci. USA, 87:3924, 1990.
5. Thein, S.L.: in The Haemoglobinopathies, edited by D.R. Higgs and D.J. Weatherall, Bailliere's Clinical Haematology, Vol. 6, page 151, W.B. Saunders Company, London, 1993.
6. Thein, S.L.: Br. J. Haematol., 80:273, 1992.

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.