Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3428-3435
Unusually Severe Heterozygous 
-Thalassemia: Evidence for an
Interacting Gene Affecting Globin Translation
P. Joy Ho,
Georgina W. Hall,
Suzanne Watt,
Nicholas C. West,
Jennifer W. Wimperis,
William G. Wood, and
Swee Lay Thein
From the MRC Molecular Haematology Unit, Institute of Molecular
Medicine, John Radcliffe Hospital, Headington, Oxford, UK; Institute of
Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia;
the Department of Haematology, Royal Free Hospital, London, UK; the
Department of Haematology, West Cumberland Hospital, Cumbria, UK; and
the Department of Haematology, Norfolk and Norwich Hospital, Norwich,
UK.
A common 
-thalassemia mutation in Asian populations is the C
T substitution at position 654 of intron 2, which leads to the activation of two cryptic splicing sites and the incorporation of
73 extra nucleotides into the mutant mRNA. Like most
-thalassemia mutations, it normally exhibits recessive
inheritance. We investigated the unusually severe phenotype in two
heterozygotes for this mutation, father and son, who had thalassemia
intermedia and an apparent dominant mode of inheritance. An increased
level of aberrantly spliced transcript in the reticulocytes of the
probands compared with asymptomatic 654
heterozygotes led us to investigate the production and processing of
654 RNA. We showed that large amounts of the
aberrant 654 transcript were detectable in
erythroblasts from one of the asymptomatic cases. The translation
product of this mRNA was not detectable in vivo, and we were unable to
demonstrate the translation of the mutant mRNA in a cell-free
translation system. Although the reticulocyte 
: mRNA
ratios in the two probands were within the range observed in the
asymptomatic heterozygotes, globin chain biosynthesis studies showed
that the probands had considerably greater : chain
imbalance. These results imply that the more severe phenotype may be
due to a second defect, possibly unlinked to the -globin
cluster, that acts at the translational or posttranslational level.
© 1998 by The American Society of Hematology.
