Beta+-thalassemia in cis of a sickle cell gene: occurrence of a promoter mutation on a beta s chromosome.
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.
Baklouti
F
F
Centre de Génétique Moléculaire et Cellulaire, Villeurbanne, France.
Ouazana
R
R
Gonnet
C
C
Lapillonne
A
A
Delaunay
J
J
Godet
J
J
D000755:Anemia, Sickle Cell / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005796:Genes; D006580:Genetic Carrier Screening; D005914:Globins / Q000235:genetics*; D006239:Haplotypes; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D009710:Nucleotide Mapping; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D015183:Restriction Mapping; D013789:Thalassemia / Q000150:complications / Q000235:genetics*
D006451:Hemoglobin, Sickle; D012333:RNA, Messenger; D005914:Globins; D004247:DNA