Lectures 12 - 13 - Michigan Medicine...1 Lectures 12 - 13 Genetics of Human Disease:...
Transcript of Lectures 12 - 13 - Michigan Medicine...1 Lectures 12 - 13 Genetics of Human Disease:...
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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