This page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
The HBA Genes in Primary Literature
Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex.
Nucleic Acids Res. 1980 Nov 11;8(21):4889-98.
Pressley, et al. [1]
This article, published in 1980, was written at a time when knowledge about the molecular defects behind thalassemia was expanding. The identity and function of all genes in the chromosome 16 globin cluster were known. Additionally, alpha (α-)thalassemia had been shown to be caused by deletions of the HBA1 and HBA2 genes (here referred to as α1 and α2) as well as by non-deletional mutations in the genes. However, few studies had shown how much variation occurred in the deletional cases of α-thalassemia. Here, the authors identify and characterize a deletion variant in one family that had not been described previously.
The study focuses on one family, of Greek origin, who had a child with symptomatic α-thalassemia, or HbH disease. The authors classify the deletional phenotypes of α-thalassemia as follows: α-thal 2 (-α/αα), now known as a silent carrier; α-thal 1 (--/αα), now known as α-thalassemia trait; HbH disease (--/-α); and the fatal Hb Barts hydrops fetalis (--/--). The authors took DNA samples from the affected child, both parents and two control subjects – one non-thalassemic individual (αα/αα), and a second, unrelated HbH disease patient. Using several restriction enzymes, the researchers digested the DNA samples from the subjects into small fragments that could be separated from each other on a gel. They then performed gel electrophoresis and autoradiography with probes that could specifically label DNA fragments from the region of chromosome 16 that contains the globin genes. By these methods, they were able to deduce that the patient had inherited a complete deletion of one α-globin gene (1 or 2 is not specified) from her father, and a 5.2 kb deletion of α2 and the 5' end of α1 from her mother. This new α-thalassemia deletion was one of only six variants identified at the time.
It struck me as a potential weakness of this study that the researchers focused their efforts on characterizing only one deletion. As this paper was published before convenient sequencing technology was available, the authors spent much of their study analyzing the fragments of their restriction digests to deduce the nature of the maternal deletion in this family. This may have prevented them from using a larger sample size, and thus they were only able to focus on the nature of one deletion. However, for this paper, I thought it would have been useful to identify the nature of the deletion in the father and the unrelated HbH patient as well.
Overall, however, it was clear that the work described in this paper represented a significant step forward in α-thalassemia research. The authors astutely suggest that “more molecular heterogeneity will be found in the α-thalassemia syndromes,” and thus further investigation should take place. Though the methods used here now seem outdated, they revealed valuable information about the molecular information about the disease. As technology has advanced, researchers can identify molecular lesions much more easily today. Not surprisingly, a multitude of deletional and non-deletional alleles have been implicated in α-thalassemia in the 30 years since this paper was published. A better understanding of these molecular causes of the disease may help to develop better detection and treatment methods. Today, prenatal screening is possible (though not widely used) to diagnose thalassemia and implement early treatment options [2].
References
- Pressley L, Higgs DR, Aldridge B, Metaxatou-Mavromati A, Clegg JB, Weatherall DJ. Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex. Nucleic Acids Res. 1980 Nov 11;8(21):4889-98. (PubMed)
- Benz EJ Jr. Newborn screening for α-thalassemia--keeping up with globalization. N Engl J Med. 2011 Feb 24;364(8):770-1. (PubMed)
