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Lectures 12 - 13

Genetics of Human Disease:Hemoglobinopathies

November 7 - 8, 2002

Learning Objectives

• Understand how the basic anatomy of a gene hasa direct bearing on the occurrence of geneticdisease.

• Know the normal and abnormal expressionpatterns of the hemoglobin genes.

• Understand the mutations that cause quantitativeabnormalities in globin.– Unequal crossing over, and every other possible type

of mutation• Recognize mutations that cause qualitative

abnormalities in globin.– Missense mutations primarily

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Textbook Figure 5.2

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Textbook Figure 6.3

Textbook Figure 6.2

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Textbook Figure 6.4

Textbook Figure 6.5

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Textbook Figure 6.14

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Textbook Figure 6.15

Textbook Figure 6.16

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_-thal is almost alwaysrelated to unequalcrossing over ordeletions.

Rarely, loss of functionof an _-globin genearises from pointmutations, but incontrast to _-thal, thesemutations are in theminority.

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Textbook Figure 6.15

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Textbook Figure 6.17

Textbook Figure 6.12

Example of unequal crossing over as a mechanism ofinactivating the _-globin gene.

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Textbook Figure 6.13

Unequal crossing over between _ and _ genes…clinically leads toa combined quantitative and qualitative abnormality (Lepore).

Notice that individuals with an anti-Lepore chromosome makenormal amounts of _ and _ , but also make the novel anti-Leporehemoglobin.

Textbook Figure 6.11

Loss of the normal termination codon near the end of _-globin gene

Loss of the normal termination codon near the end of α-globin gene

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Textbook Figure 6.19

Mutations in the _ globin promoter can give rise to _ + thalassemia

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Textbook Figure 6.20

Splicing abnormalities lead to predictable phenotypes

Textbook Figure 6.21

Most common cause of _+ thalassemia in Mediterranean isrelated to an abmormal splice acceptor site.

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Textbook Figure 6.22

Hgb E – thismutation gives riseto a quantitativeabnormality(activation of acryptic splice donorsite) and aqualitativeabnormality(missense mutationat codon 26)

Textbook Figure 6.18

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Untreated _ thalassemia

Treatment of thalassemia major

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Textbook Figure 6.24

Textbook Figure 6.25

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Textbook Figure 6.26

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NEJM 347: 1162-1168, 2002

10 large Pakistani families with hemoglobinopathies

5 large Pakistani families without hemoglobin disorders

All carriers & married couples with 2 carriers genetic counseling

NEJM 347: 1162-1168, 2002

Half-solid symbols represent those who are heterozygousfor _-thalassemia

Solid symbols represent those with _-thalassemia major

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• Average cost of Fe chelation therapy is $4,400, or10 times the average annual income.

• Treatment costs for 1 year – currently 4% ofgovernment health-expenditures.

• 183 / 591 (31%) of persons in families with anindex case tested were carriers

• All carriers reported using the information providedin counseling

• “Testing of extended families is a feasible way ofdeploying DNA-based genetic screening incommunities in which consanguineous marriage iscommon.”

Cao & Galanello, NEJM 347: 1202, 2002

Screening for _-thalassemia in Sardinia

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Summary

• Understand how the basic anatomy of a gene hasa direct bearing on the occurrence of geneticdisease.

• Know the normal and abnormal expressionpatterns of the hemoglobin genes.

• Understand the mutations that cause quantitativeabnormalities in globin.– Unequal crossing over, and every other possible type

of mutation• Recognize mutations that cause qualitative

abnormalities in globin.– Missense mutations primarily