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Hemoglobinopathies: Genetics and Screening

Explore the genetic basis of hemoglobin disorders, such as sickle cell disease and thalassemia, and learn about newborn screening for hemoglobinopathies. Understand the normal structure-function relationships of hemoglobin, expression of globin genes, and phenotypic consequences of allelic interactions. Discover the molecular aspects of hemoglobinopathies and how mutations affect protein function. This comprehensive guide discusses the most common single-gene disorders globally, offering insights into hemoglobin structure and gene expression. Gain knowledge on human hemoglobins, globin tertiary structure, gene clusters, and developmental expression patterns. Dive into clinical cases and genetic mechanisms influencing hemoglobinopathy outcomes.

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Hemoglobinopathies: Genetics and Screening

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  1. Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A705, Research Building 2012/03

  2. Required Reading Thompson &Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● Pages 237-257; ● Clinical Case Studies: 37. Sickle Cell Disease 39. Thalassemia

  3. Part I. Genetics of the Hemoglobinopathies

  4. Learning Objectives • To review the normal structure-function relationships of hemoglobin and expression of globin genes • To examine the hemoglobinopathies as disorders of hemoglobin structure, or α- or β-globin gene expression • To explore the influences of compound heterozygosity and modifier genes on hemoglobinopathy phenotypes

  5. Lecture Outline • Structure and Function of Hemoglobin • Developmental Expression of Globin Genes and Globin Switching • Sickle Cell Disease: Disorder of Hemoglobin Structure • Thalassemia: Disorder of α- or β-Globin Gene Expression • Phenotypic Consequences of Allelic Interactions and Modifier Genes

  6. Molecular Disease A disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia.

  7. The Effect of Mutation on Pr Function • Loss of Pr function (the great majority): is seen in (1)recessive diseases;(2)diseases involving haploinsufficiency, in which 50% of the gene product is insufficient for normal function; and (3)dominant negative mutations, in which the abnormal protein product interferes with the normal protein product.

  8. The Effect of Mutation on Pr Function 2. Gain of function: are sometimes seen in dominant diseases. 3. Novel property(infrequent) 4. The expression of a gene at the wrong time (Heterochronic expression), or in the wrong place (Ectopic expression), or both. (uncommon, except in cancer)

  9. Hemoglobinopathies • Disorders of the human hemoglobins • Most common single gene disorders in the world • WHO: 5% of the world’s population are carriers for clinically significant hemoglobinopatihies • Well understood at biochemical and molecular levels

  10. HbA: α2β2 • Globular tetramer • MW 64.5 kD • α-Chain • Maps to chromosome 16 • Polypeptide length of 141 amino acids • β-Chain • Maps to chromosome 11 • Polypeptide length of 146 amino acids

  11. Normal Human Hbs • Six including HbA • Each has a tetrameric structure • Two α or α-like genes • Clustered on chromosome 16 • Two non-α genes • Clustered on chromosome 11

  12. Globin Tertiary Structure • Eight helices: A-H • Two globins highly conserved • Phe 42: wedges heme porphyrin ring into heme pocket • Mut: Hb Hammersmith • His 92: covalently links heme iron • Mut: Hb Hyde Park

  13. Gene cluster: A group of adjacent genes that are identical or related. Pseudogene: DNA sequence homologous with a known gene but is non-functional.

  14. Developmental Expression of Globin Genes and Globin Switching

  15. Globin Gene Developmental Expression and Globin Switching • Classical example of ordered regulation of developmental gene expression • Genes in each cluster arranged in • Same transcriptional orientation • Same sequential order as developmental expression • Equimolar production of α-like and β-like globin chains

  16. Human Hemoglobins: Prenatal • Embryonic • 22 • Fetal: HbF • α22 • Predominates 5 wks gestation to birth • Approx 70% of total Hb at birth • <1% of total Hb in adulthood

  17. Human Hemoglobins: Postnatal • Adult: HbA • 22 •  chain synthesis increases through birth • Nearly all Hb is HbA by 3 mos of age • HbA2 • 22 • ≤2% of adult Hb • Consequence of continuing synthesis of  chains

  18. Clinical Disease: Influences of Gene Dosage and Developmental Expression • Dosage • 4 - vs. 2 -globin genes per diploid genome • Therefore, mutations required in 4 -globin genes compared with 2 -globin genes for same 100% loss of function • Ontogeny •  expressed before vs.  expressed after birth • Therefore, -chain mutations have prenatal consequences, but -chain mutations are not evidenced even in the immediate postnatal period

  19. The normal human hemoglobins at different stages of development

  20. Genetic disorders of hemoglobin 1. Structural variants: alter the globin polypeptide without affecting its rate of synthesis. 2. Thalassemias: reduced rate of production of one or more globin chains. 3. Hereditary persistence of fetal hemoglobin (HPFH) : a group of clinically benign conditions, impairing the perinatal switch from γ- toβ-globin synthesis.

  21. There are over 400 structural variants of normal hemoglobin. The 4 most common structural variants are: • Hb S(Sickle cell anemia): β chain: Glu6Val • Hb C: β chain: Glu6Lys • Hb E: β chain: Glu26Lys • Hb M(Methemoglobin):An oxidizing form of Hb containing ferric iron that is produced by the action of oxidizing poisons. Non-functional.

  22. Clinical Features of SS Disease • Presentation typically in first 2 years of life • Infections • Anemia • Failure to thrive (FTT) • Splenomegally • Dactylitis: Extremely painful swelling of hands and feet from capillary occlusion in small bones

  23. Vaso-Occlusive Infarctions • Strokes • Acute chest syndrome • Renal papillary necrosis • Autosplenectomy • Leg ulcers • Priapism • Bone aseptic necrosis • Visual loss

  24. Bone Crises • Vaso-occlusion of bones • Extremely painful • Persist for days or weeks if untreated • Treatment • Pain management • Hydration • Oxygen • Prevention • Hypertransfusion

  25. Functional Asplenia • Due to splenic infarction and other poorly understood factors • Increases susceptibility to • Pneumococcal sepsis • Salmonella osteomyelitis • Infection • Major cause of death at all ages

  26. HbS is the first variant to be discovered (1949). Its main reservoir is Central Africa where the carrier rate approximates 20%. (Heterozygous advantage) Approximately 8% of African-Americans will carry one sickle gene.

  27. Heterozygote Advantage • Mutant allele has a high frequency despite reduced fitness in affected individuals. • Heterozygote has increased fitness over both homozygous genotypes e.g. Sickle cell anemia.

  28. Multiple Origins of S Allele

  29. Multiple Origins of S Allele • HpaI restriction fragment length polymorphism (RFLP) • S allele associated with 13 kb fragment originated in West Africa • S allele with 7.6 kb fragment originated elsewhere and probably more than once • Selective pressure for multiple origins • Malaria resistance among AS heterozygotes

  30. Thalassemia: An imbalance of globin-chain synthesis • Hemoglobin synthesis characterized by the absence or reduced amount of one or more of the globin chains of hemoglobin. • α-thalassemia • β-thalassemia

  31. Varius forms of α-Thalassemia

  32. Hb Bart’s (hydrops fetalis)

  33. β-thalassemia:underproduction of the β-chain. ●β-thalassemia trait (β+/ β orβ0 /β) : .asymptomatic (β+:reduced;β0:absent) ●β-thalassemia intermedia (β+/ β+ ): . moderate anemia ●β-thalassemia major (β0 /β0 orβ+/β0 or β+/ β+ ) : . severe anemia during the first two years of life . hepatosplenomegaly . growth failure . jaundice . thalassemic facies

  34. Thalassemias can arise in the following ways: • One or more of the genes coding for hemoglobin chains is deleted. • 2. A nonsense mutation that produces a shortened chain. • 3. A frameshift mutation that produces a nonfunctional chain. • 4. A mutation may have occurred outside the codingregions.

  35. β-globin gene andβ-thalassemia

  36. Thalassemias: Pathological Effect of Globin Chain Excess • Thalassemia • Spleen from -thal homozygote • Excess -chains form a Heinz body inclusion (seen also in -thal) • Inclusions • Removed by reticulo-endothelial cells • Membranes damaged • RBCs destroyed

  37. Phenotypic Consequences of Allelic Interactions and Modifier Genes

  38. Allelic Interactions • Relatively high frequency of alleles in populations • Example • thalS • If 0 then may be like sickle cell disease • If + then may be much milder

  39. Modifier Genes: Locus Interactions • These would involve mutations in the  and  loci • Example • -thal homozygotes who also inherit an -thal allele may have less severe -thalassemia, due to less imbalance or reduced excess -globin chains

  40. The most famous authority on Hb: David Weatherall

  41. Part II. Newborn Screening for the Hemoglobinopathies

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