THE UNSTABLE HEMOGLOBINS: SOME GENETIC ASPECTS
Wajcman H1,*, Galacteros F2
*Corresponding Author: Dr. Henri Wajcman, INSERM U 468 and Service de Biochimie, Hôpital Henri Mondor AP-HP, 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
page: 3

HYPERUNSTABLE HEMOGLOBIN VARIANTS

These variants are also named dominant β-thalasse­mias, which suggests that they cannot usually be detected in peripheral blood.. They result from a large variety of mutations leading to a protein which is destroyed in the minutes or hours following its biosynthesis [29-34]. Some are due to point mutations in regions crucial for the assem­bly of the Hb tetramer, or to frameshift mutations leading to globin chains that cannot associate in functional tetram­ers. The pathophysiology of this group of variants associ­ates with an unstable β chain, which precipitates within the erythroid precursors, to an excess of free α chains, which are highly unstable molecules (Fig. 2). Thus, the resulting phenotype is close to that of thalassemia inter­media, in which the pathological manifestations result from the presence of these α chains, which, by precipitat­ing in the erythroid precursors, catalyze the formation of reactive oxygen species toxic for the membranes, leading thus to cell apoptosis and ineffective erythropoiesis.
Hyperunstable Hb variants are suspected when α thal­assemia intermedia phenotype is observed in a patient belonging to α population where thalassemic mutations are rare or absent. In these cases de novo mutations are also frequent. A problem of diagnosis exists in regions where thalassemias are frequent: in these populations, thalas­semia intermedia usually results from a compound hetero­zygous state involving two β thalassemia alleles, or the effect of an α chain triplication on a β-thal allele. A com­pound heterozygous state for a β+-thal and a mildly unsta­ble Hb variant is also possible. In the case of an hyper­unstable Hb, any of the thalassemic mutations present in the ethnic group of the patient, could be found. Since these Hbs are usually not detected by electrophoretic or chromatographic methods, molecular biology studies have to be performed. After polymerase chain reaction (PCR) amplification of the β gene a conformational analysis [denaturing gradient gel electrophoresis (DGGE), single strand conformation polymorphism (SSCP) or denaturing high performance liquid chromatography (HPLC)] may show the presence of an abnormal allele. The β gene al­most always needs to be sequenced, since a specific probe is usually not available, or only when there is a reason to suspect some specific mutation.
Hyperunstable Hbs are, in fact, a very rare cause of thalassemia intermedia. They may be distinguished from true thalassemic alleles by biosynthetic studies performed after various times of incubation. In these variants, globin chain biosynthesis is balanced at very short times of incu­bation and can become unbalanced, thalassemia-like, at longer times. When several members of a family are af­fected they all display an identical thalassemia intermedia dominant phenotype.



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