Beta+-thalassemia in cis of a sickle cell gene: occurrence of a promoter
mutation on a beta s chromosome
F Baklouti, R Ouazana, C Gonnet, A Lapillonne, J Delaunay and J Godet
Centre de Genetique Moleculaire et Cellulaire, Villeurbanne, France.
An atypical sickle cell trait with a very low level of hemoglobin S and
features of heterozygous beta-thalassemia was recently described. In vitro
globin chain synthesis strongly suggested the presence of the two
abnormalities on the same chromosome. We report the corresponding beta
S-thal gene. DNA sequence revealed a C----T base substitution in the distal
promoter element CACCC, at position-88 from the cap site, in addition to
the expected GAG----GTG mutation responsible for the structural variant
(beta 6 Glu----Val). Reticulocyte mRNA titration and transient assay of the
mutant gene in COS cells showed a defect in beta- mRNA production.
Restriction haplotype and DNA sequence analyses revealed that the doubly
mutated gene is associated with haplotype 19 (or Benin/Algeria haplotype).
In particular, we found the (AT)9(T)4 repeated sequences specifically
encountered 5' to the beta S gene of Benin Algeria type. These results
support the view that the beta S-thal gene resulted from an independent
thalassemic mutation having occurred on a beta S chromosome rather than (a)
from a beta S mutation having altered a beta-thalassemic gene or (b) from a
recombination event between two chromosomes, each carrying one of the
mutations.
Volume 74,
Issue 5,
pp. 1817-1822,
10/01/1989
Copyright © 1989 by The American Society of Hematology
