Globin Chain Synthesis in the Greek Type (^Aγ) of Hereditary Persistence of Fetal Haemoglobin

Abstract

Globin chain synthesis was studied in a family with both the Greek (Agamma) type of hereditary persistence of fetal haemoglobin and beta thalassaemia. The ratio of alpha/(gamma+beta+delta) chain synthesis in the hereditary persistence of fetal haemoglobin (HPFH) heterozygotes was 0.97 while in the HPFH/beta-thalassaemia heterozygote it was 2.14. However, calculation of the amounts of haemoglobin synthesized per cell suggests that in the HPFH/beta-thalassaemia heterozygote, the beta- and Agamma-chain genes in cis to the HPFH determinant are unable to compensate for the deficiency of chains imposed by the beta-thalassaemia gene in trans and that the increased synthesis of Hb F is directed by the gamma-chain genes located on the beta-thalassaemia chromosome. The data suggest that synthesis of beta and Agamma chains in the Greek HPFH is fixed at a 'preset' level and indicate that the defect might be due to an abnormality in the rate of transcription of the closely linked beta-, delta- and gamma-chain genes.

Biosynthetic Studies and <i>γ</i>-Chain Composition in the Greek Type of Hereditary Persistence of Fetal Hemoglobin and in Its Association with <i>β</i>-Thalässemia

“…This finding is in agree ment with the data in the literature [26], On the other hand it must be underlined that in the /1-thalassemia trait the production of Hb A attains 12 g%, while in the association reaches only 7 g, the remaining hemoglobin being formed by Hb F; in this way the «/non-«-ratio can reach the values observed in the //-thalassemia heterozygote only by remarkably increasing the y-chain synthesis. These data mean that the //-gene on the HPFH chromosome is not able to compen sate the deficiency in //-chain synthesis, as a normal gene docs, when a //-thalassemia gene is present in trans.…”

“…On the other hand, Sojroniadou el al. [26] have suggested that in the association, the HPFH chromosome is unable to increase the y-chain synthesis and that the depression of the y-genes on the //-thalassemia chromosome is responsible for the increased amount of Hb F; the pres ence of Gy -and ''/-chains in II-l and 11-2 can agree with these hypotheses.…”

“…As previously reported by Sojroniadou el a!. [26], also in our three cases, globin syn thesis gave an «/non-«-ratio within normal values. According to these data, HPFH Greek type, at least in the heterozygotes, does not seem a thalassemic condition since the decreased //-chain synthesis is complete ly balanced by a persistent production of y-chains.…”

Hematological and Hemoglobin Synthesis Studies in a Family with Hδβ -Thalassemia Trait

“…The imbalanced globin chain production, when studied, is less important than in /5-thalassemia [14]. In this family, hemato logical and clinical findings, as well as defective synthesis of non-a-chains, are more severe than in the previous described cases [4,14,22,24,27] and clearly differ ent from heterozygous HPFH [10,17,19,25,28].…”

Effects of human γ‐globin in murine β‐thalassaemia

“…Several lines of evidence suggest that c-globin gene transfer should prove curative for the b-thalassaemic patients. For example, compound heterozygotes for b-thalassaemia and deletional HPFH exhibit a very mild phenotype (Weatherall, 2001), compound heterozygotes for b-thalassaemia and a nondeletional HPFH allele exhibit a b-thalassaemia intermedia phenotype (Fessas & Stamatoyannopoulos, 1964;Sofroniadou et al, 1975;Tate et al, 1986), and compound db-thalassaemia/ b-thalassaemia heterozygotes exhibit a b-thalassaemia intermedia to mild phenotypes (Stamatoyannopoulos et al, 1969). Homozygous b 0 -thalassaemia individuals who have also coinherited an unlinked gene for heterocellular HPFH have higher levels of HbF and mild clinical course (Prchal & Stamatoyannopoulos, 1981).…”