Sequence analyses and dot-blot analyses with synthetic oligonucleotide probes have identified eight individuals in three Turkish families and one Bulgarian family with one chromosome having a C----T mutation at nucleotide position--101 relative to the Cap site of the beta-globin gene. This nucleotide is part of one of the conserved blocks of nucleotides within the promoter region; in vitro expression analyses with the chloramphenicol acetyltransferase system showed that this substitution will decrease the effectiveness of transcription. Five subjects had a thalassemia intermedia due to the additional presence of a known classical high hemoglobin (Hb) A2 beta-thalassemia mutation on the second chromosome; their hematologic condition was relatively mild. The three persons with a heterozygosity for the--101 C----T mutation had normal hematologic data without microcytosis but with high-normal levels of Hb A2 and a mild imbalance in chain synthesis. The newly discovered mutation is considered one of the silent types of beta- thalassemia. It is relatively rare because it was absent among several hundred normal and beta-thalassemia chromosomes.
We have compared the sequence of the 5′ hypersensitive site-2 (5′-HS-2) of the locus control region (LCR) from a sickle cell anemia (SS) patient homozygous for haplotype 19 and with low levels of fetal hemoglobin (HbF), with the same sequence from an SS patient homozygous for haplotype 3 and with high levels of HbF. Several nucleotide variations were present in the 5′HS-2 of the haplotype 19 individual. One is the A----G at position -10905 that creates an Sp1 binding site GCCCC (A----G)CCCC. A second is the T----G at position -10924 in a sequence that binds both erythroid and ubiquitous factors and exhibits high homology to the long terminal repeat of the Moloney leukemia viruses and Friend murine leukemia virus. Other differences were in the two AT-rich stretches of DNA, and an A----T substitution at position - 10390. Dot-blot analyses of amplified DNA from several SS patients showed that these variations are specific for beta S chromosomes with haplotype 19. We also examined the 5′HS-2 sequence from an SS patient who is homozygous for haplotype 19, but has abnormally high levels of HbF (greater than 20%). We observed a cross-over that has placed sequences similar to the 5′HS-2 of haplotype 3 in juxtaposition to the 5′ flanking regions of haplotype 19. Thus, a beta S chromosome with haplotype 19 but having a 5′HS-2 (LCR) characteristic for haplotype 3 is associated with high gamma-chain expression. We postulate that factors produced under conditions of hematopoietic stress, together with genetic determinants on the haplotype 3-like LCR sequences, allow for high level expression of gamma-globin genes.
Sequence analyses and dot-blot analyses with synthetic oligonucleotide probes have identified eight individuals in three Turkish families and one Bulgarian family with one chromosome having a C----T mutation at nucleotide position--101 relative to the Cap site of the beta-globin gene. This nucleotide is part of one of the conserved blocks of nucleotides within the promoter region; in vitro expression analyses with the chloramphenicol acetyltransferase system showed that this substitution will decrease the effectiveness of transcription. Five subjects had a thalassemia intermedia due to the additional presence of a known classical high hemoglobin (Hb) A2 beta-thalassemia mutation on the second chromosome; their hematologic condition was relatively mild. The three persons with a heterozygosity for the--101 C----T mutation had normal hematologic data without microcytosis but with high-normal levels of Hb A2 and a mild imbalance in chain synthesis. The newly discovered mutation is considered one of the silent types of beta- thalassemia. It is relatively rare because it was absent among several hundred normal and beta-thalassemia chromosomes.
A combination of 2 forms of thalassemia has been observed in a member of a South Carolina family. The proposita, a 34‐year‐old black female with hemolytic anemia, had over 50% fetal hemoglobin, an elevated level of hemoglobin A2, and in vitro imbalance in chain synthesis. Family studies revealed a δβ‐thalassemia heterozygosity in her mother and 2 sibs and a β‐thalassemia heterozygosity in her son. The fetal hemoglobin of the δβ heterozygotes was of the Gγ type (i.e., the γ chain had glycine in position 136). Consequently, it may be concluded that the propositus has Gγ‐δβ‐thalassemia‐β+ thalassemia; this is the first time that such a combination has been recognized. In 3 members of another family this same type of Gγ‐δβ‐thalassemia occurred in combination with Hb S, whereas Gγ‐β°‐HPFH (hereditary persistence of fetal hemoglobin) and Hb S were present in 1 member of a third family. Clinical features and laboratory findings were specific for each condition and permitted a clear distinction between Gγ‐δβ‐thalassemia and Gγ‐β°‐HPFH. The discussion correlates these findings with data from 80 persons in 30 families whose Hb F was elevated and contained only Gγ chains.
The nondeletional types of hereditary persistence of fetal hemoglobin (ndHPFH) concern the continued synthesis of hemoglobin (Hb) F with either G gamma or A gamma chains in amounts varying from 5% to 30%. Several mutations have been identified in either the A gamma or G gamma promoter which are considered causative to the continued production of one of the two gamma chains because the substitutions occur in sequence motifs essential for the expression characteristics of the gamma-globin gene in the 3′ position. We report the discovery of a T----C mutation at position -175 in the A gamma promoter which was associated with a greatly increased level of Hb F (with mainly A gamma) and a decreased level of Hb A in the one (Black) heterozygote who had a beta c gene in trans. The same mutation has been observed in the G gamma promoter of a Black heterozygote who had high levels of Hb F with G gamma chains only. A detailed comparison between these two individuals indicated significant differences in the levels of Hb F and Hb A which may result from an additional mutation at position -158 in the G gamma promoter.
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