Harpers

408 / CHAPTER 40∋Gγ Aγ Ψβ δ β5′ LCR 3′10 kbHemoglobinopathyβ 0 -Thalassemiaβ 0 -ThalassemiaInvertedHemoglobin Lepore(Aγδβ) 0 -ThalassemiaFigure 40–8. Schematic representation of the β-globin gene cluster and of the lesions in some geneticdisorders. The β-globin gene is located on chromosome 11 in close association with the two γ-globingenes and the δ-globin gene. The β-gene family is arranged in the order 5′-ε-Gγ-Aγ-ψβ-δ-β-3′. Theε locus is expressed in early embryonic life (as a 2 ε 2 ). The γ genes are expressed in fetal life, making fetalhemoglobin (HbF, α 2 γ 2 ). Adult hemoglobin consists of HbA (α 2 β 2 ) or HbA 2 (α 2 δ 2 ). The Ψβ is a pseudogenethat has sequence homology with β but contains mutations that prevent its expression. A locuscontrol region (LCR) located upstream (5′) from the ε gene controls the rate of transcription of the entireβ-globin gene cluster. Deletions (solid bar) of the β locus cause β-thalassemia (deficiency or absence[β 0 ] of β-globin). A deletion of δ and β causes hemoglobin Lepore (only hemoglobin α is present).An inversion (Aγδβ) 0 in this region (colored bar) disrupts gene function and also results in thalassemia(type III). Each type of thalassemia tends to be found in a certain group of people, eg, the (Aγδβ) 0 deletioninversion occurs in persons from India. Many more deletions in this region have been mapped, andeach causes some type of thalassemia.different lesions in and around the β-globin gene(Table 40–6).C. POINT MUTATIONSThe classic example is sickle cell disease, which iscaused by mutation of a single base out of the 3 × 10 9in the genome, a T-to-A DNA substitution, which inturn results in an A-to-U change in the mRNA correspondingto the sixth codon of the β-globin gene. Thealtered codon specifies a different amino acid (valinerather than glutamic acid), and this causes a structuralabnormality of the β-globin molecule. Other point mutationsin and around the β-globin gene result in decreasedproduction or, in some instances, no produc-5′ I1 I23′Figure 40–9. Mutations in the β-globin gene causing β-thalassemia. The β-globin gene is shown in the 5′to 3′ orientation. The cross-hatched areas indicate the 5′ and 3′ nontranslated regions. Reading from the 5′ to3′ direction, the shaded areas are exons 1–3 and the clear spaces are introns 1 (I 1 ) and 2 (I 2 ). Mutations that affecttranscription control (•) are located in the 5′ flanking-region DNA. Examples of nonsense mutations (),mutations in RNA processing (), and RNA cleavage mutations () have been identified and are indicated. Insome regions, many mutations have been found. These are indicated by the brackets.