University:
Franklin University
Course:
BIO-406 | Genetics
Academic year:

2020
Views:

171

Pages:

54
Author:

6AstralAdventurer

The Molecular Basis of Genetic Disease & Hemoglobinopathies 1 the online version of Mendelian Inheritance in Man listed over 5500 phenotypes for which the molecular basis is known: • autosomal • X-linked inheritance 2 The effect of mutation on protein function Mutations involving protein-coding genes have been found to cause disease through one of four different effects on protein function: 3 1. loss of function • α thalassemias • Achondroplasia • Sickle cell disease 2. gain of function 3. Acquisition of a novel property 4. the expression of a gene at the wrong time (heterochronic expression) and/or in the wrong place (ectopic expression). 4 5 Heterochronic or Ectopic Gene Expression •abnormal time or place •Cancer •continued expression in adults of the γ-globin gene, which is normally expressed at high levels only in fetal life. …hereditary persistence of fetal hemoglobin (Hb F) 6 Structure and Function of Hemoglobin • Two α-globin chains and two β(or β-like) globin chains (α2β2) Mutations that disrupt this tertiary structure invariably have pathological consequences α1 and α2 genes chromosome 16 β globin genes chromosome 11 7 8 9 10 locus control region •An approximately 20-kb domain called the locus control region (LCR) •6 kb upstream of the ε-globin gene 11 Locus Control Region A unique group of patients 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 12 LCR is required for the expression of all the genes in the β-globin cluster. 13 clinical significance of the LCR? The clinical significance of the LCR is: First: patients with deletions of the LCR fail to express the genes of the β-globin cluster. Second: knowledge of the molecular mechanisms that underlie globin switching may make it feasible to up-regulate the expression of the γ-globin gene in patients with βthalassemia (who have mutations only in the βglobin gene), because Hb F ( α2 γ2) is an effective oxygen carrier in adults who lack HbA (α2 β2 ) 14 Gene Dosage, Developmental Expression of the Globins The differences both in the gene dosage of the α- and β-globins (four α-globin and two β-globin genes per diploid genome), and in their patterns of expression during development, are important to an understanding of the pathogenesis of many hemoglobinopathies 15 Gene Dosage, Developmental Expression of the Globins Mutations in the β-globin gene are more likely to cause disease than are α-chain mutations because a single β-globin gene mutation affects 50% of the β chains, whereas a single α-chain mutation affects only 25% of the α chains. 16 THE HEMOGLOBINOPATHIES 17 The hemoglobinopathies •Structural variants •Thalassemias •Hereditary persistence of fetal hemoglobin 18 Structural variants Altering properties such as its ability to transport oxygen, or reducing its stability. Sickle cell disease, due to a mutation that makes deoxygenated β-globin relatively insoluble, changing the shape of the red cell 19 20 Thalassemias Result from the decreased abundance of one or more of the globin chains imbalance in the ratio of the α:β chains 21 Hereditary persistence of fetal hemoglobin benign conditions that impair the perinatal switch from γ-globin to β-globin synthesis. Example: • a deletion, found in African Americans, that removes both the δ- and β-globin genes continued postnatal expression of the γ-globin genes, to produce Hb F 22 23 Hemoglobin Structural Variants 24 Hemoglobin Structural Variants point mutations More than 400 abnormal hemoglobins have been described approximately half of these are clinically significant 25 Sickle Cell Disease β-globin (GAG → GTG: Glu6Val) characteristic geographical distribution, occurring most frequently in equatorial Africa 26 Sickle Cell Disease may be fatal in early childhood, although longer survival is becoming more common Severe Autosomal recessive hemolytic condition tendency of the red blood cells to become grossly abnormal in shape (i.e., take on a sickle shape) under conditions of low oxygen tension 27 Sickle Cell Disease 28 Sickle Cell Disease •Heterozygotes…sickle cell trait are generally clinically normal, but their red cells can sickle when they are subjected to very low oxygen pressure in vitro splenic infarction, especially at high altitude (for example in airplanes with reduced cabin pressure) or when exerting themselves to extreme levels in athletic competition 29 Sickle Cell Disease The βS allele has attained high frequency in malarial areas of the world because it confers protection against malaria in heterozygotes 30 Unstable Hemoglobins Point mutations that cause denaturation of the hemoglobin tetramer… insoluble and precipitate to form inclusions (Heinz bodies)… damage of the red cell membrane and cause the hemolysis of mature red blood cells 31 Unstable Hemoglobins •Hb Hammersmith (β-chain: Phe42Ser) leads to denaturation of the tetramer and consequent hemolysis phenylalanine residue is one of the two amino acids that are conserved in all globins in nature 32 Thalassemia Thalassemia: An Imbalance of GlobinChain Synthesis reduce the synthesis or stability of either the α-globin or β-globin chain to cause α thalassemia or β-thalassemia, respectively imbalance in the ratio of the α:β chains 33 Thalassemia The excess chains are insoluble and precipitate in both red cell precursors…damage the cell membrane. 34 Thalassemia Both α-thalassemia and β-thalassemia, however, have a high frequency in many populations, although α-thalassemia is more prevalent and more widely distributed. The high frequency of thalassemia is due to the protective advantage against malaria that it confers on carriers, analogous to the heterozygote advantage of sickle cell hemoglobin carriers 35 The α-Thalassemias Genetic disorders of α-globin production disrupt the formation of both fetal and adult hemoglobins. In the absence of α-globin chains, the chains from the β-globin cluster are free to form a homotetrameric hemoglobin 36 Hemoglobin with a γ4 composition is known as Hb Bart’s, and the β4 tetramer is called Hb H. ineffective oxygen carriers intrauterine hypoxia and are born with massive generalized fluid accumulation, a condition called hydrops fetalis. 37 Classification & Terminology Alpha Thalassemia •Normal •Silent carrier •Minor •Hb H disease •Barts hydrops fetalis αα/αα - α/αα -α/-α --/αα --/-α --/-- 38 39 The β-Thalassemias •the decrease in β-globin production causes a hypochromic, microcytic anemia •an imbalance in globin synthesis due to the excess of α chains. •The excess α chains are insoluble and precipitate 40 The β-Thalassemias Most individuals with two βthalassemia alleles have thalassemia major, a condition characterized by severe anemia and the need for lifelong medical management 41 Symbolism Other Thalassemia •Greek letter used to designate globin chain: β 42 Symbolism Other Thalassemia +: Indicates diminished, but some production of globin chain by gene: β+ 43 Symbolism Other Thalassemia :Indicates no production of globin chain by gene: 0 β0 44 The β-Thalassemias In contrast to α-globin, however, the β chain is important only in the postnatal period. 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. 45 The β-Thalassemias The synthesis of the major adult hemoglobin, HbA, is reduced. The level of Hb F is increased in βthalassemia Single base pair substitutions rather than to deletions 46 The β-Thalassemias treatment of the thalassemias is based on correction of the anemia and the increased marrow expansion by blood transfusion and on control of the consequent iron accumulation by the administration of chelating agents. Bone marrow transplantation effective option too. is 47 The β-Thalassemias 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. 48 The β-Thalassemias The diagnosis of thalassemia minor can be supported by hemoglobin electrophoresis, which generally reveals an increase in the level of Hb A2 (α2δ2) 49 Complex Thalassemias The large deletions that cause the complex thalassemias remove the βglobin gene plus one or more other genes—or the LCR—from the βglobin cluster. Reduced expression of β-globin and one or more of the other β-like chains. 50 Complex Thalassemias These disorders are named according to the genes deleted, for example, (δβ)0-thalassemia or (Aγδβ)0thalassemia, and so on. 51 52 Hereditary Persistence of Fetal Hemoglobin A second group of large β-globin gene cluster deletions of medical significance are those that leave at least one of the γ genes intact (such as the English deletion) •δβ0-thalassemia •a benign condition called hereditary persistence of fetal hemoglobin (HPFH) 53 Hereditary Persistence of Fetal Hemoglobin That is due to disruption of the perinatal switch from γ-globin to β-globin synthesis. Homozygotes with either of these conditions are viable because the remaining γ gene or genes are still active after birth, instead of switching off as would normally occur. As a result, Hb F (α2γ2) synthesis continues postnatally at a high level and compensates for the absence of Hb A. 54