Genetic disorders of α- globin production disrupt the formation of both fetal and adult hemoglobins, causing intrauterine as well as postnatal dis ease. In the absence of α- globin chains with which to associate, the chains from the β- globin cluster are free to form a homotetrameric hemoglobin. Hemoglobin with a γ4 composition is known as Hb Barts, and the β4 tetramer is called Hb H. Because neither of these hemoglobins is capable of releasing oxygen to tissues under normal conditions, they are completely ineffective oxygen carriers. Consequently, fetuses with severe α- thalassemia and high levels of Hb Barts suffer severe intrauterine hypoxia and develop massive generalized fluid accumulation: a condition called hydrops fetalis. In milder α- thalassemias, an anemia develops because of the gradual precipitation of the Hb H in the erythrocyte. The formation of Hb H inclusions in mature red cells and the removal of these inclusions by the spleen damages the cells, leading to their premature destruction.

Deletions of the α- Globin Genes. The most common molecular causes of α- thalassemia are gene deletions. The high frequency of deletions in the α- chain genes, compared with, for example, the β- chain genes, is a con sequence of having two identical α- globin genes on each chromosome 16. This arrangement of tandem homologous α- globin genes facilitates misalignment, due to homologous pairing and subsequent recombination between the α1 gene domain on one chromosome and the corresponding α2 gene region on the other (Fig. 1). Evidence supporting this pathogenic mechanism of nonallelic homologous recombination is provided by reports of individuals with a triplicated α- globin gene complex. Deletions or other alterations of one, two, three, or all four copies of the α- globin gene cause a proportionately severe hematologic abnormality (Table 1).

Fig1. The probable mechanism underlying the most common form of α- thalassemia, which is due to deletions of one of the two α- globin genes on a chromosome 16. Misalignment, homologous pairing, and recombination between the α1 gene on one chromosome and the α2 gene on the homologous chromosome result in the deletion of one α- globin gene. (Redrawn from Kazazian HH: The thalassemia syndromes: Molecular basis and prenatal diagnosis in 1990, Semin Hematol 27:209– 228, 1990.)

Table1. Clinical States Associated With α- Thalassemia Genotypes

Individuals with two normal and two abnormal α- globin genes are said to have α- thalassemia trait.

This can result from either of two genotypes (−−/ αα or −α/ −α), differing in whether the deletions are in cis or in trans. The α- thalassemia trait is distributed throughout the world. However, heterozygosity for deletion of both copies of the α- globin gene in cis (−−/ αα genotype) is largely restricted to Southeast Asians. Offspring of two carriers of this deletion allele may receive two −−/ −− chromosomes, leading to Hb Barts (γ4 ) and hydrops fetalis. In other populations, however, α- thalassemia trait is usually the result of the trans −α/ −α genotype, which cannot give rise to −−/ −− offspring.

In addition to α- thalassemia variants that result in deletion of the α- globin genes, variants that delete only the lCR of the α- globin complex can cause α- thalassemia. In fact, similar to the observations with respect to the β- globin lCR, such deletions were critical for demonstrating the existence of this regulatory element at the α- globin locus.

Other Forms of α- Thalassemia. In all the classes of α- thalassemia described earlier, deletions in the α- globin genes or variants in their cis- acting sequences account for the reduction of α- globin synthesis. Other types of α- thalassemia occur much less commonly. One important rare form of α- thalassemia is ATR- X syndrome, which is associated with both α- thalassemia and intellectual disability. It illustrates the importance of epigenetic packaging of the genome in the regulation of gene expression. The X chromosome ATRX gene encodes a chromatin remodeling protein that functions, in trans, to activate the expression of the α- globin genes. The ATRX protein belongs to a family of proteins that function within large multiprotein complexes to change DNA topology. ATR- X syndrome is one of several monogenic diseases that result from variants in chromatin remodeling proteins (chromatinopathies).

ATR- X syndrome was initially recognized as unusual because the first families in which it was identified were northern Europeans, a population in which the deletion forms of α- thalassemia are uncommon. All affected individuals were males with severe intellectual disability, together with a wide range of other abnormalities, including characteristic facial features, skeletal defects, and urogenital malformations. This diversity of phenotypes suggests that ATRX regulates the expression of numerous other genes besides the α- globins.

In those with ATR- X syndrome, the reduction in α- globin synthesis is due to accumulation at the α- globin gene cluster of a histone variant called macroH2A. This accumulation reduces α- globin gene expression and causes α- thalassemia. To date, all variants in the ATRX gene associated with ATR- X syndrome involve partial loss of function, leading to hematologic defects that are mild, compared with those seen in the classic forms of α- thalassemia.

Individuals with ATR- X syndrome have abnormalities in DNA methylation patterns to indicate that the ATRX protein is also required to establish or maintain the methylation pattern in certain domains of the genome. This may be by modulating access of the DNA methyltransferase enzyme to its binding sites. This finding is noteworthy because variants in MECP2, which encodes a protein that binds to methylated DNA, cause Rett syndrome by disrupting the epigenetic regulation of genes in regions of methylated DNA, leading to neurodevelopmental regression. Normally, ATRX and the MeCP2 protein interact; impairment of this interaction due to ATRX variants may contribute to the intellectual disability seen in ATR- X syndrome.

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فرقة العباس (عليه السلام) تختتم خدماتها المقدمة للزائرين في سامراء

موكب العتبتين المقدستين يحيي ذكرى استشهاد الإمام الهادي (عليه السلام) في سامراء

العتبة العسكرية المقدسة تكرّم وفد العتبة العباسية المقدسة لمشاركته في تقديم الخدمات للزائرين

العتبة العباسية المقدسة تختتم مشاركتها في تقديم الخدمات لزائري مرقد الإمامين العسكريين (عليهما السلام)

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كنز غذائي على طبقك.. ماذا تفعل السبانخ بجسمك؟

ما لا يتوقعه أحد.. "سر غذائي" في الجبن الدسم

لتحسين الهضم والنوم.. هذا أفضل وقت لتناول العشاء

10 طرق بسيطة وغير مألوفة لحرق المزيد من السعرات يوميا

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سابقة بعالم الطيران.. طائرة تقرر الهبوط بنفسها بعد ظرف طارئ

"الإنفلونزا الخارقة" تكتسح دول العالم.. وتثير قلقا كبيرا

مرحلة ما قبل الأعراض.. دواء جديد يستهدف "شرارة" الزهايمر

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مواضيع ذات صلة

Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The β- Thalassemias

Hemoglobin Structural Alterations

Transient neonatal diabetes

Permanent neonatal diabetes

Fragile X Syndrome

Polyglutamine Disorders

Monogenic Causes of Diabetes : Glucokinase MODY and pregnancy

Monogenic Causes of Diabetes : Glucokinase MODY

Monogenic Causes of Diabetes: Maturity- onset diabetes of the young

Deletion and Duplication Syndromes

Uniparental Disomy