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Moderate reduction of beta-globin gene transcript by a novel mutation in
the 5' untranslated region: a study of its interaction with other genotypes
in two families
PJ Ho, J Rochette, CA Fisher, B Wonke, MK Jarvis, A Yardumian and SL Thein
MRC Molecular Haematology Unit, John Radcliffe Hospital, Oxford, UK.
We have identified two individuals of Greek Cypriot origin with thalassemia
intermedia. Molecular analysis has shown that each individual is a compound
heterozygote for a previously described beta zero thalassemia allele and a
novel mutation, C-->G in position +33, in the 5' untranslated region of
the beta globin gene. In both families the beta +33 allele is associated
with the same beta haplotype (-++- ) suggesting that it is likely to be of
a single origin, beta-cDNAs from normal and mutant beta alleles were
isolated from peripheral blood reticulocytes using the technique of reverse
transcription-polymerase chain reaction. Because the beta +33 (C-->G)
mutation creates a cutting site for the restriction enzyme NlalV, we could
demonstrate by differential restriction analysis that the beta gene with
+33 mutation showed 25% to 35% residual activity compared with normal. The
additive effect of this moderate deficit in beta globin production with the
beta zero thalassemia mutation would explain the clinical phenotypes
observed in the two probands. In contrast, two siblings of one proband who
were also compound heterozygotes for the same beta thalassemia mutations,
as well as heterozygotes for a nondeletional alpha thalassemia variant, and
two other compound heterozygotes for the beta +33 and a beta+ thalassemia
allele were completely asymptomatic. Individuals heterozygous for the beta
+33 C-G mutation alone are clinically and hematologically silent, with
normal red blood cell indices and normal levels of hemoglobin (Hb) A2. A
direct relationship between genotypic and phenotypic severity is clearly
demonstrated in these cases with obvious implications for prenatal
diagnosis.
Volume 87,
Issue 3,
pp. 1170-1178,
02/01/1996
Copyright © 1996 by The American Society of Hematology
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