Bio 362 Human Genetics Spring 2008
Dwarfism study sheet for February 12th
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Background web readings and review papers:
In the Ornitz and Marie review paper, focus mainly on the endochondral ossification information and less on intermembraneous bone formation.
What are the important events and cell types that characterize bone development?
What are the various types of dwarfism? What are some of the symptoms found in types other than achondroplasia? What other category of disorder (besides dwarfism) is caused by FGFR mutations?
What are FGFs and FGFRs? How many are there? Is there a one-to-one relationship?
In what parts of the body is FGFR3 expressed? What is its normal role?
What are the symptoms of achondroplasia?
What is the mode of inheritance for achondroplasia?
What is unusual about the origin of spontaneous achondroplasia mutations? (see supplementary Vajo paper pp 30-31)
What are the common mutations found in people with achondroplasia? What effects do these mutations have on protein function?
What other disorders are associated with FGFR3, and how does the nature of mutations correlate with severity of phenotype?
What disorders are associated with mutations in FGFR2?
Which FGFRs are expressed when and in what regions during bone development?
What happens in mice with a targeted disruption of FGFR3? What other mouse models exist?
What signalling pathways regulate endochondral ossification? Try to get a general sense of what Figure 4A in Ornitz and Marie depicts.
How do FGFRs affect those pathways?

Chen et al., 1999 (Questions from Cecie and Katie):
1) What is the main goal of the researchers?
2) What two approaches did they take to answer their question?
3) What happens to FGR3 when it is activated?
4) How did the researches visualize its activation?
5) How is it that a gain of function mutation can cause a decrease in long bone growth?
6) Compare figure 4 panels d-f with panel g, what is happening?
7) What is the range of phenotypes across the 369 mutant homozygotes and heterozygotes compared with wild type in figures 3 and 4?
8) What changes happen at the cellular level in each cell type (chondrocytes and osteoblasts) in figures 5 and 6?

Aikawa et al., 2001:
Into what finding from the Chen paper are these authors delving more deeply? What questions are they trying to answer?
What's the general role of p21?
What observation regarding p21 in chondrocytes made it a promising protein for FGFR3 researchers to study?
What cell type do the researchers use? Why might one be a little suspicious of using this general cell type in this kind of study?
In general, how are those concerns allayed by the data in Figs 1 and 2?
Fig 1: How was this experiment performed?
Fig 2: Here are some hints to help understand this figure: propidium iodide binds DNA and makes it fluoresce. Using flow cytometry you can sort cells based on the intensity of the fluorescence in each cell. How much DNA does a cell have during G1? S phase? G2? mitosis? How did the researchers utilize flow cytometry to show the effect of FGF treatment on RCS cells?
Fig 3: What kind of experiment is this? How do these data confirm the findings from Fig 2?
Fig 4: How does immunoprecipitation work? How does treatment with FGF change what p21 is doing in the RCS cells?
Fig 5: What's the experimental setup? How is this fundamentally different from in previous figures? What does FGF treatment cause?
Fig 6: What's the experimental setup? How does the use of a knockout mouse confirm p21's role in FGF-mediated inhibition of cell division?
Fig 7: How is this different from Fig 6?
Why are these findings important?
These data conflict with data in another paper. Read the abstract of this paper at http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9887329&dopt=Abstract
to get the gist of what the other group did. How do you reconcile the two sets of findings?