Slideshow is from the University of Michigan Medical School's M1 Patients and Populations: Medical Genetics Sequence. View additional course materials from Open.Michigan: openmi.ch/med-M1PatientsPopulations

1. Author(s): David Ginsburg, 2009
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3. M1 Patients and Populations:
Genetics of Human Disease:
Hemoglobinopathies
David Ginsburg, MD
Fall 2008

4. Learning Objectives
• Understand how the basic anatomy of a gene has a
direct bearing on the occurrence of genetic disease.
• Know the normal and abnormal expression patterns of
the hemoglobin genes.
• Understand the mutations that cause quantitative
abnormalities in globin.
– Unequal crossing over, and every other possible type of
mutation
• Recognize mutations that cause qualitative
abnormalities in globin.
• Understand the molecular basis of sickle cell anemia.

5. kb 0 10 20 30 40 50 60
ε
Gγ
Aγ
ψβ1 δ
β
LCR
CHROMOSOME 11
ζ
ψζ
ψα2
ψα1 α2 α1 θ1
CHROMOSOME 16
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 5.2

6. Source Undetermined

7. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.4

8. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.5

9. Zephyris (wikimedia)

10. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.3

11. Regents of The University of Michigan
Review of Medical Physiology 22E; Figure 27.19

12. Quantitative Abnormalities of
Hemoglobin
• α Thalassemia
– deficiency of α globin chains
• β Thalassemia
– deficiency of β globin chains
• HPFH
– Hereditary persistence of fetal
hemoglobin

13. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.14

14. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.16

15. Source Undetermined

16. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.15

17. Normal peripheral blood smear
Hgb H disease
Source Undetermined ( All Images)

18. Map of gene
frequencies of
thalassemias and
endemic malaria
removed
Miller LH. Nature, 383:480, 1996.

19. Gelehrter, Collins and Ginsburg:
Principles of Medical Genetics 2E;
Figure 6.16

20. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.19

21. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.20

22. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.21

23. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.22

24. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.18

25. Normal peripheral blood smear
β-Thalassemia (homozygous)
Source Undetermined ( All Images)

26. Image of boy
with
Thalassemia
removed

27. Gelehrter, Collins and Ginsburg: Principles of Medical
Genetics 2E; Figure 6.24

28. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.25
Source Undetermined

29. Image of amino acid
residue variations in
beta thalassemia
hemoglobin removed
Original Image From Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.6

30. Qualitative Abnormalities of
Hemoglobin
• Silent Variants
• Unstable hemoglobins
– Heinz body hemolytic anemia
• Methemoglobinemia
• High affinity hemoglobins
– polycythemia (↑hematocrit and hemoglobin)
• Low affinity hemoglobins
– mild anemia (↓hematocrit and hemoglobin)
• Hemoglobin S
• Hemoglobin C

31. Regents of The University of Michigan
Gelehrter, Collins and Ginsburg: Principles of Medical
Genetics 2E; Figure 6.7

32. SC SS AA AC
sickle Nl trait
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.9

33. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.8

34. Oxygenated and Deoxygenated Sickle Red Blood Cell
Bunn & Forget. Hemoglobin: Molecular, Genetic and Clinical Aspects. 1986.

35. Hemoglobin SS Disease
Source Undetermined Source Undetermined

36. Complications of Sickle Cell
Anemia
• autosplenectomy
• hyposthenuria
• Infections
– encapsulated organisms-- pneumococcus
– salmonella, staph
• Painful crises
• Bone infarcts, aseptic necrosis
• Stroke
• Acute chest syndrome
• Hand-foot syndrome
• Chronic organ damage

37. Source Undetermined

38. Regents of The University of Michigan
Review of Medical Physiology 22E; Figure 27.19

39. Source Undetermined
Hb S only occurs on 4 haplotypes…only occurred 4 times in history

40. Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 4.2
Hb S is a balanced polymorphism
* homozygotes (1 in 500) are selected against
* heterozygotes (1 in 12) are selected for

41. Sickle Cell Anemia:
Treatment
• IV fluids
• Analgesia
• Infection
– penicillin prophylaxis
– vaccines
• Oxygen
• Transfusion
• Erythropoietin
• Hydroxyurea
• Bone Marrow Transplantation

42. Learning Objectives
• Understand how the basic anatomy of a gene has a
direct bearing on the occurrence of genetic disease.
• Know the normal and abnormal expression patterns of
the hemoglobin genes.
• Understand the mutations that cause quantitative
abnormalities in globin.
– Unequal crossing over, and every other possible type of
mutation
• Recognize mutations that cause qualitative
abnormalities in globin.
• Understand the molecular basis of sickle cell anemia.

43. Additional Source Information
for more information see: http://open.umich.edu/wiki/CitationPolicy
Slide 5: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 5.2
Slide 6: Source Undetermined
Slide 7: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.4
Slide 8: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.5
Slide 9: Zephyris (wikimedia)
Slide 10: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.3
Slide 11: Regents of The University of Michigan; Review of Medical Physiology 22E, Figure 27.19
Slide 13: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.14
Slide 14: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.16
Slide 15: Source Undetermined
Slide 16: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.15
Slide 17: Source Undetermined ( All Images)
Slide 18: Miller LH. Nature, 383:480, 1996.
Slide 19: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.16
Slide 20: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.19
Slide 21: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.20
Slide 22: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.21
Slide 23: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.22
Slide 24: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.18
Slide 25: Source Undetermined ( All Images)
Slide 27: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.24
Slide 28: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.25; Source Undetermined
Slide 29: Original Image From Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.6
Slide 31: Regents of The University of Michigan; Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E,
Figure 6.7
Slide 32: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.9
Slide 33: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 6.8
Slide 34: Bunn & Forget. Hemoglobin: Molecular, Genetic and Clinical Aspects. 1986.
Slide 35: Soure Undetermined; Source Undetermined

44. Slide 37: Source Undetermined
Slide 38: Regents of The University of Michigan; Review of Medical Physiology 22E, Figure 27.19
Slide 39: Source Undetermined
Slide 40: Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E, Figure 4.2