The Molecular Basis of  -Thalassemia

Abstract

The globin gene disorders including the thalassemias are among the most common human genetic diseases with more than 300,000 severely affected individuals born throughout the world every year. Because of the easy accessibility of purified, highly specialized, mature erythroid cells from peripheral blood, the hemoglobinopathies were among the first tractable human molecular diseases. From the 1970s onward, the analysis of the large repertoire of mutations underlying these conditions has elucidated many of the principles by which mutations occur and cause human genetic diseases. This work will summarize our current knowledge of the a-thalassemias, illustrating how detailed analysis of this group of diseases has contributed to our understanding of the general molecular mechanisms underlying many orphan and common diseases.

Classification of the Disorders of Hemoglobin

“…As discussed briefly here, and in much more detail in Thein (2013), Higgs (2013), Nienhuis and Nathan (2012), and Musallam et al (2012), mutations of globin genes that impair synthesis give rise to thalassemia and anemia of varying degree. In addition, well-defined clinical and hematologic phenotypes are associated with mutations that alter the structure of globin subunits, discussed in more detail in Thom et al (2013).…”

The Role of the Inherited Disorders of Hemoglobin, the First “Molecular Diseases,” in the Future of Human Genetics

“…On the contrary, as pointed out in a recent review (44), it is hard to find a single example in which what has been learned from studying these genes-involving enhancers, locus control regions, boundary elements, promoters, RNA processing, and many aspects of protein translation, structure, and function-has been limited to these genes rather than helping to establish the principles of genome organization and how this relates to gene expression. Similarly, the mechanisms by which these mutations arose, including chromosomal rearrangement, telomere truncations, homologous and illegitimate recombination, gene conversion, copy number variation, abnormal methylation, the involvement of antisense RNAs, and many others, have now been established as common to many human diseases and yet were first recognized in the hemoglobin disorders.…”

“…Two of them are associated with mental retardation (ATR) (112); one of these is encoded on chromosome 16 (ATR16), and the other is encoded on the X chromosome (ATRX). The former, caused by subtelomeric 16p deletions (44), is associated with relatively mild degrees of mental retardation together with a variety of developmental abnormalities. Although it may arise de novo, often one parent carries a preexisting balanced translocation that the child inherits in an unbalanced fashion.…”

“…Mutations of ATRX are also found in elderly patients with myelodysplasia. The complex actions of the ATRX gene product-which have, incidentally, revealed the critical role of chromatin remodeling in the expression of the α globin genes-are reviewed elsewhere (37,44). than justified; over a period of one year, six different research groups found the same mutation in β globin genes from unrelated persons of Mediterranean background.…”

The Genotypes of α-Thalassemia and Genotypes Frequencies of α-Thalassemia in Hatay

“…α-talasemi, talasemi türlerinden yalnızca bir tanesidir ve otozomal resesif olarak kalıtılır. Fenotipi çok değişkenlik göstermekle birlikte, mikrositik hiperkromik anemi ile karakterizedir (2). Hemoglobindeki α-globin zincirinin eksikliği ya da azalması ile karakterize edilen α-talasemide, hastalığın en hafif formuna tek gen heterozigot (α-/αα), en ağır formuna ise iki gen homozigot (--/--) mutasyonları neden olur.…”