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Chapter 1
Discovery Questions
Discovery Questions
This activity contains 46 questions.
Go to Online Mendelian Inheritance in Man (OMIM; database of human diseases and genes) and see if you can diagnose this disease. Spend only about five to ten minutes at this site.
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Try the National Center for Biotechnology Information (NCBI), "Genes and Diseases" (different organization from OMIM) and see if you can diagnose this disease. Again, spend only five to ten minutes on this.
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Go to OMIM again and see if you can diagnose this disease. Spend only about five to ten minutes at this site.
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Try NCBI Genes and Diseases again and see if you can diagnose this disease. Spend no more than five to ten minutes on this.
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What can you conclude about individual number 12 in BB's extended family (see Figure 1.2a)? Identify this individual's gender and probable disease status.
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Go to OMIM and see if you can diagnose this disease with a quick search. Spend only about five to ten minutes at this site.
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Go to NCBI Genes and Diseases and use the search window to see if you can diagnose BB's disease in five to ten minutes.
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Does GG represent an exception to the rule for X-linked diseases, or is she consistent with it? Explain your answer.
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Search OMIM to see if you can diagnose this disease. Spend only about five minutes at this site.
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Go to protein blast and use BLASTp (protein sequence search tool) to see if you can diagnose this disease. To assist you, use the following amino acid sequence from the locus of interest, which was conserved in all family members: NICKECPIIGFRYRSLKHFNYDICQSCFF. Save in electronic form the proteins you find with this search. We will return to these hits.
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Go to Protein Data Bank (PDB; 3D protein structure database), enter the code "1dxx," and click on "Find a Structure." This file contains four copies of the amino portion of the full protein. Click on "View Structure" and view this fragment using the QuickPDB method (this file is a homotetramer). Find the location for the mutations found in GG and BB (see Table 1.1). Where do these mutations lie within the protein? Look at the location of the mutation in the secondary structure.
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Find and highlight the sequence DVQKKTFTKW (amino acids 15-24). What kind of secondary structure does the peptide help form? This answer will be useful later, so note the location of the peptide.
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Another form of muscular dystrophy, Becker muscular dystrophy (BMD), affects primarily males. Whereas DMD is diagnosed on average by age 4.6 years, BMD patients do not show signs until they are in their twenties. They develop less severe symptoms and live much longer. Assuming that these two diseases are caused by mutations in dystrophin, hypothesize a mechanism to explain the difference in clinical symptoms.
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Another phenotype of DMD patients is mental retardation. Hypothesize how a "muscle" protein like dystrophin could cause brain deficiencies. (This issue is addressed again in Section 1.2.)
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What experiment would you perform to find out where the utrophin protein is normally located? What tissue would you use for this experiment, and why?
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Would you expect any diseases associated with the loss of utrophin?
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Why do you think there are no diseases associated with a loss of function in utrophin?
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Go to the immunoprecipitation animation and study the banding pattern produced for each lane. Explain the banding pattern for each lane.
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Which lane or lanes in the animation best represents what you would see in an
mdx
mouse or a DMD patient?
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Use Figures 1.7 and 1.8 to answer these questions. a. Predict the phenotype if a person were homozygous for an actin deletion. b. Predict the phenotype if a person were homozygous for the deletion of the entire dystroglycan complex. c. Predict the phenotype if a person were homozygous for a deletion of only one protein from the dystroglycan complex. d. Predict the phenotype if a person were homozygous for a sarcospan deletion.
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Given your predictions, explain why it makes sense that DMD and BMD were so easily identified as genetic diseases. Why was dystrophin initially identified as the only cause of muscular dystrophy?
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Predict a molecular mechanism that could produce the differences seen in DMD and BMD.
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Based on these diagrams and your predictions, do you think there are other human diseases that would present symptoms similar to those of muscular dystrophy?
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Do the children have a dominant or a recessive disease? What are the genotypes of the parents?
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The father was not willing to participate, because of his religious beliefs. Would having access to his tissue change your interpretation of Figure 1.9?
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Search OMIM and find the chromosomal location for the four genes in Figure 1.9. Spell out the Greek letters when you search. Determine whether the genes are linked or unlinked.
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Given their chromosomal location, do you think that all eight of the alleles were mutated in the two children, or is there another, more likely, answer? Refer to Figures 1.7 and 1.8.
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Go to NCBI and select "protein" from the search menu at the top left corner. Enter the word "sarcoglycan" and search the protein database. How many different human sarcoglycan genes are there? You know there are at least four, but can you find any more?
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What is the name of the disease associated with mutations in sarcoglycans? You might want to click on your results from Discovery Question 28, or search OMIM.
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Is it possible to have two separate pathways (structural and nonstructural) that cause diseases with similar symptoms?
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Using the circuit diagram in Figure 1.13c, make some predictions about nonstructural causes of muscular dystrophies. Choose any of the proteins discussed so far.
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Go to PubMed and search for "muscular dystroph*" (the asterisk is a wild card, so you will get hits for "dystrophy," "dystrophies," and "dystrophin"). Look for papers that suggest nonstructural causes for muscular dystrophies.
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Using the circuit diagram in Figure 1.15, identify the three functional levels in the model.
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Using Ervasti's circuit diagrams, make a prediction of how there could be a signaling pathway that is also perturbed by the weak linkage between the plasma membrane and ?-actin. Even if you do not know what all these proteins do, use the circuitry to suggest possibilities.
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Formulate a hypothesis that can explain the data shown in Figure 1.18. Use the data in this chapter to support your hypothesis.
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If you could obtain tissue from any patient included in Figure 1.18, which ones would you like to study? Why?
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Modify your earlier hypotheses (Discovery Questions 30 and 31) to explain how muscular dystrophies might be digenic in nature, or at least have two pathways as their molecular causes.
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What effect does a lack of dystrobrevin have on the dystroglycan complex?
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