The β- thalassemias share many features with α- thalassemia. In β- thalassemia, the decrease in β- globin production causes a hypochromic, microcytic anemia. An imbalance in globin synthesis is due to the excess of α chains. The latter are insoluble and precipitate (see Fig. 1) in both red cell precursors (causing ineffective erythropoiesis) and mature red cells (causing hemolysis) because they damage the cell membrane. In contrast to α- globin, however, the β chain is important only in the postnatal period. Consequently, the onset of β- thalassemia is not apparent until a few months after birth, when β- globin normally replaces γ- globin as the major non– α chain (see Fig. 2B). Only the synthesis of the major adult hemoglobin, Hb A, is reduced. The level of Hb F is increased in β- thalassemia, not because of a reactivation of the γ- globin gene expression that was switched off at birth, but because of selective survival and perhaps increased production of the minor population of adult red blood cells that contain Hb F.

Fig1. Visualization of one pathologic effect of the deficiency of β chains in β- thalassemia: the precipitation of the excess normal α chains to form a Heinz body in the red blood cell. Peripheral blood smear and Heinz body preparation. The peripheral smear (A) shows “bite” cells with pitted- out semicircular areas of the red blood cell membrane as a result of removal of Heinz bodies by macrophages in the spleen, causing premature destruction of the red cell. The Heinz body preparation (B) shows increased Heinz bodies in the same specimen when compared to a control (C). (From Hoffman R, Furie B, McGlave P, et al: Hematology: Basic principles and practice, ed 5, 2008, Elsevier.)

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.)

In contrast to α- thalassemia, the β- thalassemias are usually due to single nucleotide variants rather than to deletions (Table 1). In many regions of the world where β- thalassemia is common, there are so many different β- thalassemia variants that individuals with this condition are more likely to be compound heterozygotes (i.e., carrying two different β- thalassemia alleles) than to be homozygotes for one allele. Most individuals with two β- thalassemia alleles have thalassemia major: a condition characterized by severe anemia and the need for lifelong medical management. When the β- thalassemia alleles allow so little production of β- globin that no Hb A is present, the condition is designated β0- thalassemia. Clinically, affected individuals are dependent on red blood cell transfusions. If some Hb A is detectable, the affected individual has β+- thalassemia. Although the severity of the clinical disease depends on the combined effect of the two alleles present, until recently, survival into adult life was unusual.

Table1. The Molecular Basis of Some Causes of Simple β- Thalassemia

Infants with homozygous β- thalassemia present with anemia once the postnatal production of Hb F decreases—generally before 2 years of age. At present, in most countries, treatment of the thalassemias is based on correction of the anemia and the increased marrow expansion by blood transfusion; the consequent excess iron accumulation is controlled by administration of chelating agents. Bone marrow transplantation is effective, but this is an option only if an HlA- matched family member can be found. Gene therapy options are now emerging in clinical practice.

Carriers of one β- thalassemia allele are clinically well and are said to have thalassemia minor. Such individuals have hypochromic, microcytic red blood cells and may have a slight anemia that can be misdiagnosed initially as iron deficiency. The diagnosis of thalassemia minor can be supported by hemoglobin electrophoresis, which generally reveals an increase in the level of Hb A2 (α2 δ2 ). In many countries, thalassemia minor is sufficiently common to require diagnostic distinction from iron deficiency anemia and to be a frequent source of referral for prenatal diagnosis of affected homozygous fetuses.

α- Thalassemia Alleles as Modifier Genes of β- Thalassemia. In human genetics, one of the best examples of a modifier gene comes from co-existence of β- thalassemia and α- thalassemia alleles in a population. In such populations, β- thalassemia homozygotes may also inherit an α- thalassemia allele. The clinical severity of the β- thalassemia is sometimes ameliorated by the presence of the α- thalassemia allele, which acts as a modifier. The imbalance of globin chain synthesis that occurs in β- thalassemia (due to the relative excess of α chains) is reduced by the decrease in α- chain production that results from the α- thalassemia gene deletion.

β- Thalassemia, Complex Thalassemias, and Hereditary Persistence of Fetal Hemoglobin. Almost every type of DNA variant known to reduce the synthesis of an mRNA or protein has been identified as a cause of β- thalassemia. The following overview of these genetic defects is, therefore, instructive about variant mechanisms in general, by describing the molecular basis of one of the most common and severe genetic diseases in the world. Variants of the β- globin gene complex are separated into two broad groups with different clinical phenotypes. One group, which accounts for the great majority of patients, impairs the production of β- globin alone and causes simple β- thalassemia. The second group consists of large deletions that cause the complex thalassemias, in which the β- globin gene is removed, as well as one or more of the other genes— or the lCR— in the β- globin cluster. Finally, we are informed about the regulation of globin gene expression through some deletions within the β- globin cluster that do not cause thalassemia, but rather, a benign phenotype termed the hereditary persistence of fetal hemoglobin (i.e., the persistence of γ- globin gene expression throughout adult life).

Molecular Basis of Simple β- Thalassemia. Simple β- thalassemia results from a remarkable diversity of molecular defects, predominantly single nucleotide variants, in the β- globin gene (Fig. 3; see Table 1). Most variants causing simple β- thalassemia lead to a decrease in the abundance of the β- globin mRNA. These include promoter variants, RNA splicing variants (the most common), mRNA capping or tailing variants, and frameshift or nonsense variants that introduce premature termination codons within the coding region of the gene. A few hemoglobin structural alterations also impair processing of the β- globin mRNA, as exemplified by Hb E (described later).

Fig3. Representative point variants and small deletions that cause β- thalassemia. Note the distribution of variants throughout the gene and that the variants affect virtually every process required for the production of normal β- globin. More than 100 different β- globin point variants are associated with simple β- thalassemia.

RNA Splicing Variants. Most β- thalassemia cases with a decreased abundance of β- globin mRNA have abnormalities in RNA splicing. Dozens of defects of this type have been described, and their combined clinical burden is substantial. These variants have acquired high visibility because their effects on splicing are often unexpectedly complex, and analysis of the altered mRNAs has contributed extensively to knowledge of the sequences critical to normal RNA processing. The splice defects are separated into three groups (Fig. 4) depending on the region of the unprocessed RNA in which the variant is located.

Fig4. Examples of variants that disrupt normal splicing of the β- globin gene to cause β- thalassemia. (A) Normal splicing pattern. (B) An intron 2 variant (IVS2- 2A>G) in the normal splice acceptor site aborts normal splicing. This variant results in the use of a cryptic acceptor site in intron 2. The cryptic site conforms perfectly to the consensus acceptor splice sequence (where Y is either pyrimidine, T or C). Because exon 3 has been enlarged at its 5′ end by inclusion of intron 2 sequences, the abnormal alternatively spliced messenger RNA (mRNA) made from this mutant gene has lost the correct open reading frame and cannot encode β- globin. (C) An intron 1 variant (G > A in nucleotide 110 of intron 1) activates a cryptic acceptor site by creating an AG dinucleotide and increasing the resemblance of the site to the consensus acceptor sequence. The globin mRNA thus formed is elongated (19 extra nucleotides) at the 5′ side of exon 2; a premature stop codon is introduced into the transcript. A β+ thalassemia phenotype results because the correct acceptor site is still used, although at only 10% of the wild- type level. (D) In the Hb E defect, the missense variant (p.Glu26lys) in codon 26 in exon 1 activates a cryptic donor splice site in codon 25 that competes effectively with the normal donor site. Moderate use is made of this alternative splicing pathway, but the majority of RNA is still processed from the correct site, and mild β+ thalassemia results. (Modified from Stamatoyannopoulos G, Grosveld F: Hemoglobin switching. In Stamatoyannopoulos G, Majerus PW, Perlmutter RM, et al, editors: The molecular basis of blood diseases, ed 3, Philadelphia, 2001, WB Saunders.)

• Splice junction variants include those at the canonical 5′ donor or 3′ acceptor splice junctions of the introns or in the consensus sequences surrounding the junctions. The critical nature of the conserved GT dinucleotide at the 5′ intron donor site and of the AG at the 3′ intron acceptor site is demonstrated by the complete loss of normal splicing that results from variants in these dinucleotides (see Fig. 4B). Inactivation of the normal acceptor site elicits the use of other acceptor- like sequences elsewhere in the RNA precursor molecule. These alternative sites are termed cryptic splice sites because they are not used by the splicing apparatus if the correct site is available. Cryptic donor or acceptor splice sites can be found in either exons or introns.

• Intronic variants enhance the use of a cryptic splice site by making it more similar or identical to the nor mal splice site. The activated cryptic site then competes with the normal site, with variable effectiveness. This reduces the abundance of the normal mRNA by decreasing splicing from the correct site, which remains perfectly intact (see Fig. 4C). Cryptic splice site variants are often leaky, which means that some use of the normal site occurs, producing a β+- thalassemia phenotype.

• Coding sequence changes that affect splicing result from variants in the open reading frame that activate a cryptic splice site in an exon, whether or not they also change the amino acid sequence (see Fig. 4D). For example, a mild form of β+- thalassemia results from a variant in codon 24 (see Table 1) that activates a cryptic splice site but does not change the encoded amino acid (both GGT and GGA code for glycine); this is an example of a syn onymous variant that is not neutral in its effect.

Nonfunctional mRNAs. Some mRNAs are nonfunctional and cannot direct the synthesis of a complete poly peptide, because the variant generates a premature stop codon, which prematurely terminates translation. Two β- thalassemia variants near the amino terminus exemplify this effect (see Table 1). In one (p. Gln39Ter), the failure in translation is due to a single nucleotide substitution that creates a nonsense variant. In the other, a frameshift variant results from a single base pair deletion early in the open reading frame, removing the first nucleotide from codon 16, which normally encodes glycine. In the reading frame that results, a pre mature stop codon is quickly encountered downstream, well before the normal termination signal. Because no β- globin is made from these alleles, both types of non functional mRNA variants cause β0- thalassemia in the homozygous state. In some instances, frameshifts near the carboxyl terminus of the protein allow most of the mRNA to be translated normally or to produce elongated globin chains, resulting in a variant hemoglobin rather than null alleles.

In addition to ablating the production of the β- globin polypeptide, premature stop variants, including the two described earlier, often lead to reduced abundance of the abnormal mRNA; indeed, the mRNA may be undetectable. The mechanism under lying this phenomenon—called nonsense- mediated mRNA decay, appears to be restricted to nonsense codons located more than 50 bp upstream of the final exon- exon junction.

Defects in Capping and Tailing of β- Globin mRNA. Several β+- thalassemia variants highlight the critical nature of post-transcriptional modifications of mRNAs. For example, the 3′ uTR of almost all mRNAs ends with a polyA sequence, and if this sequence is not added, the mRNA is unstable. As introduced in Chapter 3, polyadenylation of mRNA first requires enzymatic cleavage of the mRNA, which occurs in response to a signal for the cleavage site, AAuAAA, that is found near the 3′ end of most eukaryotic mRNAs. Individuals with a substitution that changes the signal sequence to AACAAA produce only a minor fraction of correctly polyadenylated β- globin mRNA.

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Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The α- 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