VI-c.   Alpha-Globin Gene Mutations Occurring on a Chromosome With the -Alpha(3.7 kb) or the -Alpha(4.2 kb) Deletion

There are several alpha chain variants which result from mutations in the alpha2alpha1 hybrid gene of the chromosome with the 3.7 kb deletion or in the only remaining alpha1-globin gene of the chromosome with the 4.2 kb deletion. These alpha-thal-2 linked abnormal Hbs usually occur in the heterozygote at significantly higher levels [~30-35% in -alpha(X)/alphaalpha] than in heterozygotes with four alpha-globin genes [20-25% in alpha(X)alpha/alphaalpha or alphaalpha(X)/alphaalpha]. Examples are:

1.   Hb Chad [alpha23(B4)Glu->Lys]

(1). The GAG->AAG mutation occurred in a Surinam family on a chromosome with the 3.7 kb (type I) deletion. The quantity of the alpha-Chad chain averaged 31.5% in its carriers [alpha(Chad)(-3.7 kb)/alphaalpha], and 43% in the two carriers with an additional alpha-thal-2 homozygosity [-alpha(Chad)(-3.7 kb)/ -alpha(-3.7 kb)]. These quantities are considerably higher than those reported for families from Chad, China, and Japan; the low levels of 14.5-24% Hb in these persons suggest a mutation on a chromosome with two alpha-globin genes.

2.   Hb Hasharon [alpha47(CE5)Asp->His]

Senno et al (2) report levels of ~32% in a family from Northern Italy; the carriers were also heterozygous for the -3.7 kb deletion and the two abnormalities were linked. Studies of families from different parts in the USA, Australia, and Austria have indicated lower levels (15.3-20.4% in eight individuals of six families). The mutation (GAC->CAC) was found in the alpha2-globin gene and none of the individuals had an alpha-thal-2 heterozygosity (unpublished data).

3.   Hb G-Philadelphia [alpha68(E17)Asn->Lys]

(3-5). This variant in the Black population is associated with the 3.7 kb deletion; its quantity in heterozygotes[-alpha(X)/alphaalpha] varies between 30 and 35%, and the alpha-thal-2 in homozygotes [-alpha(X)/-alpha] between 40 and 45%. The mutation involves an AAC->AAG change at codon 68. Other individuals, Caucasians of Italian origin, have a lesser amount (~25% Hb G) and four alpha-globin genes; the mutation concerns an AAC->AAA change at codon 68 of the alpha2 gene [alpha(X)alpha/alphaalpha]. Fig. 23 shows the distribution of the quantities of Hb G in numerous heterozygotes and in nine heterozygotes with a homozygosity for the 3.7 kb alpha-thal-2 deletion.

[Figure not yet available.]

FIG. 23. The percentages of Hb G-Philadelphia in heterozygotes with four, three, or two alpha-globin genes. Data obtained in the author's laboratory by DEAE-cellulose or cation exchange HPL chromatography.

4.   Hb Q-Thailand [alpha74(EF4)Asp->His]

(6,7). This variant is due to a GAC->CAC mutation at codon 74 of the alpha1-globin gene of an alpha-thal-2 chromosome with the 4.2 kb deletion. The quantities in heterozygotes [-alpha(X)/alphaalpha] from China, Hong Kong, Canada (five families) ranged from 27.4-34.9% (unpublished data). Patients with Hb Q-Hb H disease [-alpha(X)/- -] only produce Hb Q, Hb H, and Hb Bart's.

5.   Hb Duan [alpha75(EF4)Asp->Ala]

(8). This rare variant, found in a few Chinese families, is due to a GAC->GCC mutation at codon 75 of the alpha1-globin gene on the chromosome with the 4.2 kb deletion [-alpha(X)/alphaalpha]. The heterozygote has ~37% Hb Duan.

6.   Hb Stanleyville-II [alpha78(EF7)Asn->Lys]

(9). This variant was present in one homozygote and three heterozygotes of a family from the Congo. The mutation (AAC-> AAG) was found on the alpha2alpha1 hybrid gene of a chromosome with the 3.7 kb deletion [-alpha(X)/alphaalpha]. The heterozygote had 32-35% of alpha(X) and the homozygote had 100% alpha(X) [-alpha(X)/-alpha(X)]. There are also older reports (10-13) of lower quantities (~24%) in simple heterozygotes.

7.   Hb J-Cape Town [alpha92(FG4)Arg->Gln

(14,15). This CGG->CAG mutation at codon 92 has been found to be associated with the 3.7 kb deletion [-alpha(X)/alphaalpha]. The quantity in four such persons varied between 29.2 and 33.8% (unpublished data).

8.   Hb J-Tongariki [alpha115(GH3)Ala->Asp]

(16-18). The GCC->GAC mutation occurs on a chromosome with the 3.7 kb (type III) deletion. The quantity of alpha(X) varies between 45 and 50% in the heterozygote [presumably -alpha(X)/-alpha] and 100% in the homozygote [-alpha(X)/-alpha(X)].

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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.