1
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
2
3
Textbook Figure 5.2
4
Textbook Figure 6.3
Textbook Figure 6.2
5
Textbook Figure 6.4
Textbook Figure 6.5
6
Textbook Figure 6.14
7
Textbook Figure 6.15
Textbook Figure 6.16
8
_-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.
9
Textbook Figure 6.15
10
Textbook Figure 6.17
Textbook Figure 6.12
Example of unequal crossing over as a mechanism ofinactivating the _-globin gene.
11
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
12
Textbook Figure 6.19
Mutations in the _ globin promoter can give rise to _ + thalassemia
13
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.
14
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
15
Untreated _ thalassemia
Treatment of thalassemia major
16
Textbook Figure 6.24
Textbook Figure 6.25
17
Textbook Figure 6.26
18
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
19
• 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
20
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
Top Related