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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