Α Thalassemia

a-Globin is encoded by the two adjacent genes, al and a2. Although it is clearly established that both a-globin genes are expressed, their relative contributions to a-globin messenger RNA (mRNA) and protein synthesis are not fully defined. Furthermore, changes that may occur in a-globin gene activity secondarily to the loss of function of one or more of these genes (a-thalassemia [Thall) have not been directly investigated. This study further defines the expression of the two human a-globin genes by determining the relative levels of al and a2 mRNA in the reticulocytes of normal individuals and in individuals heterozygous for the common 3.7-kilobase deletion within the a-globin gene cluster that removes the a2-globin gene (the rightward type aThal-2 deletion). To quantitate accurately the ratio of the two a-globin mRNAs, we have modified a previously reported S1 nuclease assay to include the use of 32P end-labeled probes isolated from al-and a2-globin complementary DNA recombinant plasmids. In individuals with a normal a-globin genotype (as determined by Southern blot analysis Iaa/aal), a2-globin mRNA is present at an average 2.8-fold excess to al. In individuals heterozygous for the rightward type a-Thal-2 deletion (-a/aa) the ct2/al mRNA ratio is 1:1. These results suggest that the loss of the a2-globin gene in the a-Thal-2 deletion is associated with a 1.8-fold compensatory increase al-globin gene expression.

Section: Methodsmentioning

confidence: 99%

Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion.

Liebhaber¹,

Cash²,

Main³

1985

“…The presence of a short-lived red cell population has been described in HbH disease (29), while the electron-microscopic appearances of the HbCS red cell precursors are closer to those of HbH disease than to the different a-thalassemia carrier states. Similarly, the gel filtration experiments show that, as in HbH disease, HbCS ho- The acs-mutation occurs in the a2-globin gene (28,30,32) and, while mRNA quantitation suggests a twofold excess of a2-over alI-mRNA in normal individuals (28,30,32), this difference appears to be compensated for by differential translation, producing equal proportions of a-chain from each gene (33). There is no evidence from quantitation of other abnormal a-chain variants that the output of a-chains directed by each gene differs significantly, and an individual homozygous for an a2-gene deletion (-a'4 2/-a 42) is hematologically indistinguishable from any other individual with an a-gene deletion condition in which only two genes remain active (unpublished observation).…”

Section: Hematologic Studiesmentioning

confidence: 99%

Hematologic and biosynthetic studies in homozygous hemoglobin Constant Spring.

Derry¹,

Wood²,

Pippard³

et al. 1984

Abstract. The elongated a-globin chains of hemoglobin Constant Spring (acs chain of HbCS) are produced in low amounts such that the acs-gene acts as a form of a-thalassemia; yet in the homozygous state the pathophysiological effects of this mutant are more severe than in the corresponding conditions that result from aglobin gene deletions. In studies designed to examine this discrepancy, we have demonstrated that a significant proportion of red cells produced in an HbCS homozygote has a much reduced red cell life span. Contrary to previous reports, we have been able to demonstrate the expected deficit in a-chain production in this condition and have shown that both the cessation of globin chain synthesis in vitro and the destruction of the excess 3-chains occur unusually rapidly. Comparison with various deletion forms of a-thalassemia suggests that, in terms of intracellular globin chain precipitates and free ,8-chain pool, homozygous HbCS red cells more closely resemble those of HbH disease, with three ofthe four a-genes inactivated, than they do the more comparable a-thalassemia carriers with only two genes deleted.

“…A variety of mutations within this cluster result in deficient or absent synthesis of a-globin and the consequent group of genetic disorders known as the a-thalassemias (4). Most commonly, a-thalassemia results from the deletion of one or both of the a-globin genes (5). Less commonly, a-globin gene function is altered by a defect that does not produce a gross gene deletion (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

An initiation codon mutation (AUG----GUG) of the human alpha 1-globin gene. Structural characterization and evidence for a mild thalassemic phenotype.

Moi¹,

Cash²,

Liebhaber³

et al. 1987

a-globin is encoded by two adjacent genes, al and a2. Recent evidence suggests that these genes are not equally expressed and that the a2-globin gene encodes the majority of a-globin. This finding would predict that a thalassemic mutation of the a2-globin gene would result in a more severe loss of a-chain synthesis than a similar mutation in the al-globin gene. In a previous study we described a nondeletion a-thalassemia defect in the a2-globin gene resulting from an AUG --ACG initiation codon mutation. In the present study we describe a different initiation codon mutation, AUG -GUG, present in the al-globin gene. The al-and a2-globin gene initiation codon mutations result in similarly lowered levels of encoded mRNA. Despite the similarity of these two mutations, the a2 mutant results in a more severe loss of a-globin synthesis and a more severe clinical a-thalassemia phenotype than the corresponding al-globin gene mutation. This difference reflects the dominant role of a2-globin gene in overall a-globin synthesis.