Bio 362 Human Genetics Spring 2008
Marfan Syndrome study sheet for January 22
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Background readings (including textbook chapters and Ramirez and Dietz review paper)
What are the symptoms, diagnostic criteria, and treatments for Marfan Syndrome?
What genes are associated with the syndrome? What do they encode? What are the roles of the gene products?
The old standard view of Marfan was that defective fibrillin led directly to weaker connective tissue simply because fibrillin is a component of extracellular matrix. How has our overall view become more complex regarding the mechanisms underlying Marfan syndrome?
How might you explain the variability in symptoms seem in different patients?
What is the general idea of recombination mapping? In humans, what genetic markers are used?
Why do you need "informative meioses" to do linkage analysis?
What are lod scores? How are they calculated? How are they used? (we will do an exercise in class on this topic)
What is autozygosity mapping, and when is it useful?

Kanulainen et al. 1990
What was the goal of this paper? What was known prior to this study?
What approach did the authors take? Who were their subjects?
Figure 1: what do the plusses and minuses mean? (The authors don't word their explanation very well)
How is the diagnosis of each individual depicted?
Can you deduce the genotypes of any of the individuals for which the genotype is not shown?
Which of the three markers is not completely linked to the disease? Which individuals tell you that?
How does Table 1 relate to Figure 1?
How does Figure 2 relate to Table 1?
What are the general difficulties encountered in trying to map a disease gene by linkage analysis?
For what did this study set the stage?

Dietz et al., 1991
What converging approaches led to this study?
How does Figure 1 correspond to what we saw in the previous paper?
Figure 2: What was the goal here? What is SSCP analysis? Why does only one patient show a difference?
Explain what specific mutation was found in patient E.S. (text and Figure 3A-B). Do you automatically assume that that mutation causes the disease? What other experiments were done (e.g. Figure 3C)?
How does gene homology in other species support the conclusion?
What do the authors speculate regarding Marfan mutations in other families?

Byers, 2004
By what mechanism (haploinsufficiency, dominant negativity, or gain of function) is Marfan syndrome autosomal dominant? What are the supporting data? (Since this isn't a research paper, the data aren't shown here; they are simply described and summarized.)
What is the mechanistic connection between fibrillin and TGF-beta? What are the supporting data?
What are the implications for treating the disease?