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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.

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)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  Thalassemia –deficiency of  globin chains  Thalassemia –deficiency of  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, 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  -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 SCAC 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 Oxygenated and Deoxygenated Sickle Red Blood Cell

Hemoglobin SS Disease 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)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 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, 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 Slide 35: Soure Undetermined; Source Undetermined Additional Source Information for more information see:

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