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Author(s): David Ginsburg, 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/
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Genetics of Human Disease: Hemoglobinopathies
David Ginsburg, MD
M1 Patients and Populations:
Fall 2008
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.
Gγ Aγ ψβ1 δ ε β
ζ ψζ ψα2 ψα1 α2 α1 θ1
10 0 20 30 40 50 60 kb
CHROMOSOME 11 CHROMOSOME 16
LCR
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 5.2
Source Undetermined
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.4
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.5
Zephyris (wikimedia)
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.3
Regents of The University of Michigan
Review of Medical Physiology 22E; Figure 27.19
Quantitative Abnormalities of Hemoglobin
• α Thalassemia – deficiency of α globin chains
• β Thalassemia – deficiency of β globin chains
• HPFH – Hereditary persistence of fetal
hemoglobin
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.14
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.16
Source Undetermined
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.15
Normal peripheral blood smear
Hgb H disease
Source Undetermined ( All Images)
Miller LH. Nature, 383:480, 1996.
Map of gene frequencies of
thalassemias and endemic malaria
removed
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.16
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.19
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.20
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.21
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.22
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.18
Normal peripheral blood smear
β-Thalassemia (homozygous)
Source Undetermined ( All Images)
Image of boy with
Thalassemia removed
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.24
Source Undetermined
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.25
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
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
Regents of The University of Michigan
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.7
AA Nl
SS sickle
SC AC trait
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.9
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 6.8
Bunn & Forget. Hemoglobin: Molecular, Genetic and Clinical Aspects. 1986.
Oxygenated and Deoxygenated Sickle Red Blood Cell
Hemoglobin SS Disease
Source Undetermined Source Undetermined
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
Source Undetermined
Regents of The University of Michigan
Review of Medical Physiology 22E; Figure 27.19
Hb S only occurs on 4 haplotypes…only occurred 4 times in history
Source Undetermined
Hb S is a balanced polymorphism * homozygotes (1 in 500) are selected against * heterozygotes (1 in 12) are selected for
Gelehrter, Collins and Ginsburg: Principles of Medical Genetics 2E; Figure 4.2
Sickle Cell Anemia: Treatment
• IV fluids • Analgesia • Infection
– penicillin prophylaxis – vaccines
• Oxygen • Transfusion • Erythropoietin • Hydroxyurea • Bone Marrow Transplantation
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.
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
Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy
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