To illustrate in greater detail the concepts introduced in the first section of this chapter, we now turn to disorders of hemoglobin. These hemoglobinopathies are collectively the most common monogenic diseases in humans, and major contributors to global morbidity. The World Health Organization estimates that more than 5% of the world’s population are heterozygous carriers of genetic variants associated with clinically important disorders of hemoglobin. Hemoglobinopathies are also important because their molecular and biochemical pathology is better understood than perhaps that of any other group of genetic diseases. Indeed, our understanding of the basic anatomy of a gene  arose in large part from studying these prototypical monogenic disorders of hemoglobin. Before the hemoglobinopathies are discussed in depth, it is important to briefly introduce the normal aspects of the globin genes and hemoglobin biology.

Structure and Function of Hemoglobin

 Hemoglobin is the oxygen carrier in vertebrate red blood cells. Each hemoglobin molecule consists of four subunits: two α- (or α- like) globin chains and two β- (or β- like) globin chains. Each subunit is composed of a poly peptide chain, globin, and a prosthetic group, heme. The latter is an iron- containing pigment that combines with oxygen to give the molecule its oxygen- transporting ability (Fig. 1). The predominant adult human hemoglobin, Hb A, has an α2 β2 structure in which the four chains are folded and fit together to form a globular tetramer.

Fig1. The structure of a hemoglobin subunit. Each subunit has eight helical regions, designated A to H. The two most conserved amino acids are shown: p.His92, the histidine to which the iron of heme is covalently linked; and p.Phe42, the phenylalanine that wedges the porphyrin ring of heme into the heme “pocket” of the folded protein. See discussion of Hb Hammersmith and Hb Hyde Park, which have substitutions for p.Phe42 and p.His92, respectively, in the β- globin molecule.

As with all proteins that have been strongly conserved throughout evolution, the tertiary structure of globins is constant; virtually all globins have seven or eight helical regions (depending on the chain) (see Fig. 1). Variants that disrupt this tertiary structure invariably have pathologic consequences. In addition, variants that substitute a highly conserved amino acid or that replace one of the nonpolar residues—which form the hydrophobic shell that excludes water from the interior of the molecule, are likely to cause a hemoglobinopathy (see Fig. 1). like all proteins, globin has sensitive areas, in which variants cannot occur without affecting function, and insensitive areas, in which variations are more freely tolerated.

The Globin Genes

In addition to Hb A, with its α2 β2 structure, there are five other normal human hemoglobins, each of which has a tetrameric structure like that of Hb A, consisting of two α or α- like chains and two non- α chains (Fig. 2A). The genes for the α and α- like chains are clustered in a tan dem arrangement on chromosome 16. Note that there are two identical α- globin genes, designated α1 and α2, on each homologue. The β- and β- like globin genes, located on chromosome 11, are close family members that, as described in Chapter 3, undoubtedly arose from a common ancestral gene (see Fig. 2A). Illustrating this close evolutionary relationship, the β- and δ- globins differ in only 10 of their 146 amino acids.

Fig2. Organization of the human globin genes and hemoglobins produced in each stage of human development. (A) The α- like genes are on chromosome 16, the β- like genes on chromosome 11. The curved arrows refer to the switches in gene expression during development. (B) Development of erythropoiesis in the human fetus and infant. Types of cells responsible for hemoglobin synthesis, organs involved, and types of globin chain synthesized at successive stages are shown. (A, Redrawn from Stamatoyannopoulos G, Nienhuis AW: Hemoglobin switching. In Stamatoyannopoulos G, Nienhuis AW, leder P, et al, editors: The molecular basis of blood diseases, Philadelphia, 1987, WB Saunders; B, redrawn from Wood WG: Haemoglobin synthesis during fetal development, Br Med Bull 32:282– 287, 1976.)

Developmental Expression of Globin Genes and Globin Switching

 The expression of the various globin genes changes during development, a process referred to as globin switching (see Fig. 2B). Note that the genes in the α- and β- globin clusters are arranged in the same transcriptional orientation and, remarkably, the genes in each cluster are situated in the same order in which they are expressed during development. The temporal switches of globin synthesis are accompanied by changes in the principal site of erythropoiesis (see Fig. 2B). The three embryonic globins are made in the yolk sac from the third to eighth weeks of gestation, but at approximately the fifth week, hematopoiesis begins to move from the yolk sac to the fetal liver. Hb F (α2 γ2 ), the pre dominant hemoglobin throughout fetal life, constitutes ~70% of total hemoglobin at birth. In adults, however, Hb F represents only a few percent of the total hemoglobin, although this can vary from less than 1% to ~5% in different individuals.

β- chain synthesis becomes significant near the time of birth, and by 3 months of age almost all hemoglobin is of the adult form: Hb A (α2 β2 ) (see Fig. 2B). In diseases due to variants that decrease the abundance of β- globin, such as β- thalassemia (see later section), strategies to increase the normally small amount of γ- globin (and therefore of Hb F [α2 γ2 ]) produced in adults are proving to be successful in ameliorating the disorder.

The Developmental Regulation of β- Globin Gene Expression: The Locus Control Region

Elucidation of the mechanisms that control expression of the globin genes has provided generalizable insights into both normal and pathologic biologic processes. The expression of the β- globin gene is only partly controlled by the promoter and two enhancers in the immediate flanking DNA. A requirement for additional regulatory elements was first suggested by the identification of individuals who had no gene expression from any of the genes in the β- globin cluster, even though the genes themselves (including their individual regulatory elements) were intact. These informative patients were found to have large deletions upstream of the β- globin complex that removed an ~20 kb domain—now called the locus control region (LCR), located ~6 kb upstream of the ε- globin gene (Fig. 3). The resulting disease, εγδβ- thalassemia, is described later in this chapter. These cases show us that the lCR is required for the expression of all genes in the β- globin cluster.

Fig3. The β- globin locus control region (LCR). Each of the five regions of open chromatin (arrows) contains several consensus binding sites for both erythroid- specific and ubiquitous transcription factors. The precise mechanism by which the lCR regulates gene expression is unknown. Also shown is a deletion of the lCR that has led to εγδβ- thalassemia, which is discussed in the text. (Redrawn from Kazazian Jr HH, Antonarakis S: Molecular genetics of the globin genes. In Singer M, Berg P, editors: Exploring genetic mechanisms, Sausalito, 1997, university Science Books.)

The lCR is defined by five DNase I hypersensitive sites (see Fig. 3): genomic regions that are unusually open to certain proteins (including the enzyme DNase I) used experimentally to reveal potential regulatory sites. Within the context of the epigenetic packaging of chromatin, these sites maintain an open chromatin configuration that gives transcription factors access to the regulatory elements that mediate the expression of each of the β- globin genes in erythroid cells. The lCR, along with its associated DNA- binding proteins, interacts with the genes of the β- globin locus to form a nuclear domain called the active chromatin hub, where β- globin gene expression takes place. The sequential switching of gene expression that occurs among the five members of the β- globin gene complex during development results from the sequential association of the active chromatin hub with the different genes in the cluster, as the hub moves from the most proximal gene in the complex (the ε- globin gene in embryos) to the most distal (the δ- and β- globin genes in adults).

The clinical significance of the lCR could extend beyond those individuals with deletions of the lCR who fail to express the genes of the β- globin cluster. Components of the lCR may prove relevant to gene therapy for disorders of the β- globin cluster, wherein a goal is for the therapeutic normal copy of the gene in question to be expressed at the correct time in life and in the appropriate tissue. Knowledge of the molecular mechanisms that underlie globin switching may also make it feasible to up- regulate the expression of the γ- globin gene in those with β- thalassemia (who have variants only in the β- globin gene) because Hb F (α2 γ2 ) is an effective oxygen carrier in adults who lack Hb A (α2 β2 ).

Gene Dosage, Developmental Expression of the Globins, and Clinical Disease

The differences, both in the gene dosage of the α- and β- globins (four α- globin and two β- globin genes per dip loid genome) and in their patterns of expression during development, are important to an understanding of the pathogenesis of many hemoglobinopathies. A variant in a β- globin gene affects 50% of the β chains, whereas a single α- chain variant affects only 25% of the α chains. β- globin variants have no prenatal consequences because γ- globin is the major β- like globin before birth, with Hb F constituting 75% of the total hemoglobin at term (see Fig. 2B). In contrast, because α chains are the only α- like components of hemoglobin 6 weeks after conception, α- globin variants cause severe disease in both fetal and postnatal life.

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مواضيع ذات صلة

The Relationship Between Genotype and Phenotype in Genetic Disease

Effect of Pathogenic Variants on Protein Function

HNF1A and HNF4A (Transcription factor MODY)

Categories of Epigenetic disorders

Epigenetics in Development

Mosaicism

Pseudoautosomal inheritance

Characteristics of autosomal recessive inheritance

Patterns of Inheritance

Pedigrees

Genotype and Phenotype

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