Bio 363 Human Genetics, Spring 2013
Progeria study sheet
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Background web reading
How does the incidence of Hutchinson-Gilford progeria syndrome (HGPS) compare to the incidence of other genetic disorders we have covered this semester?
What are the symptoms? What characteristics of normal aging are missing in progeria patients?

Worman et al. , 2009
Read the first three pages up to the "Diseases" heading carefully.
Then starting at the "Diseases" heading, focus on only the parts of the paper that cover progeria and mouse models thereof. (Skim the material on cardiomyopathy and other disorders if you're interested.)

Eriksson et al., 2003, and De Sandre-Giovannoli et al., 2003
These two papers are from competing labs and were published at roughly the same time in different journals. Look at the dates of submission, acceptance, and publication for each paper, and, after reading the papers, assess the relative quality and completeness of each.
Erikkson et al., 2003
Out of all the patients listed in Table 1, which were the three odd ones that caused the researchers to focus on the correct region of chromosome 1?
What is uniparental disomy (UPD)? Look it up.
What data are summarized in Figure 1a? How did they indicate UPD in two of the three odd patients?
Use Figure 1b-c to explain what's going on in the third odd patient.
How did all the data fit together to indicate a candidate region? How many genes were there? Why was LMNA interesting?
What mutations were found in the other patients?
Use Figure 2 to explain precisely how the most common mutation leads to the defect. How was the phenomenon predicted by the mutation confirmed?
What's going on with patient AG10677 and the E145K mutation?
What subcellular defects are seen in an affected person (Figure 3)? What cell type is examined here?
De Sandre-Giovannoli et al., 2003
Supplementary data for this paper are on Louise
When you read the first sentence of the third paragraph, what are you left wondering?
Why do they say that Lamin-A may not be made from the normal allele of patients (see top of third column in main paper and supplementary data part A)? How can that possibly be?
Is the Western blot (in the supplementary data) consistent with that in the Eriksson et al. paper?
Is Fig 1c-d consistent with what you saw in the Eriksson et al. paper?
Would you have added anything to Figure 1?

Scaffidi and Misteli, 2005
Supplementary data for this paper are on Louise and can also be found online.
In Figure 1, what proteins are stained in each column?
Is the nuclear phenotype in cells from progeria patients fixed by adding an extra laminA/C gene?
What is the point of the GFP in Fig. 1c?
What do the percentages mean in Fig. 1?
What is FRAP, and what does the experiment in Fig. 1d tell us about wild type lamin A in the presence of the mutant form?
How is the setup in Fig. 1f different from 1c? How does it confirm the findings from 1c?
What is a morpholino? What does it mean to be a 25-mer?
In Fig. 2, what cell types were used, and from what individuals? What was done with the extracts from each cell type?
What different sets of primers were used in 2b vs. 2e? What does presence of the morpholino cause? How is Fig. 1g different than 1b and 1e?
How did they determine that the effects on splicing don't affect lots of genes non-specifically? Find the supplementary data online.
Fig.3: Does treatment with the morpholino rescue the phenotype??
Supplementary Figure 3: The rescue of the phenotype does NOT require the cells to do what? Why were these experiments important? How was the setup different in part b vs. part c?
Why were there so many supplementary data files? Why not just include them in the paper?