Biochemical and Molecular Genetics III:

Clinical Correlations of Molecular Defects

Lecture 19

November 16 (Friday), 2001

Required Reading: Principles of Medical Genetics

1998 Williams and Wilkins

Pages: 137-143

• You will be responsible for learning about the molecular basis for disease processes through understanding the examples of hemophilia as presented in your textbook. The basic concepts that are important to know are nicely illustrated in the figures presented in the textbook and you should be sure to understand the general concepts illustrated in each of the figures.

• For hemophilia you should understand the basic concepts of the disease process especially as related to:

• Genotype - What kinds of mutations occur? How do they occur? Understand the wide variety of different types of mutations that have been described in Hemophilia A and the potential mechanisms underlying the mutations — especially for any novel mechanisms of mutation (eg. the recurrent inversion, mutational hot spots) that are discussed in the book.

• Inheritance pattern — How are Hemophilia type A and B inherited? Can both women and men be affected? Why or why not? Understand that although most female carriers of hemophilia A are asymptomatic that some female may exhibit symptoms and understand why this may occur. Why are most female carriers asymptomatic?

• Phenotype — Why are there different degrees of severity in hemophilia? How do the levels of severity of disease correlate with the amount of circulating Factor 8 levels. What are the basic molecular mechanisms underlying hemophilia A and B?

• Molecular diagnosis as discussed in the textbook. Understand how cloning of the gene involved in this condition has enabled accurate prenatal diagnosis by direct mutational analysis or linkage analysis and

• Other points to ponder:

• Although you will need to know the clotting cascade during your medical school career and will need to memorize and regurgitate the information for other classes, you do not need to memorize it for this class.... Really!

• Understand how cloning of the gene involved has also the way for the development of recombinant factor used for treatment and is also paving the way for development of gene transfer applications. Consider how you might design gene therapy for hemophilia. What levels of circulating Factor 8 would you need to achieve? Where might you want to express the gene? (You will have a gene therapy lecture later on in this course).

• Understand that defects at different points in the clotting cascade may cause different bleeding disorders and be familiar with Hemophilia B.

• Understand that gene expression of the Factor IX gene and the resulting clinical phenotype may change during different times of life and know one mechanism why this might happen.

• Understand why in both Hemophilia A and B that 1/3 of all mutations are thought to arise de novo (Haldane).