Bio 362 Human Genetics Spring 2008
Deafness study sheet for January 29th
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Background information:
In a hearing person, what chain of events occurs when a sound enters the ear?
What goes on in the cochlea?
What is the role of the Organ of Corti?
Within the Organ of Corti, what are the roles of the hair cells? How are potassium ions involved?
What are the types of genetic deafness? What are the abbreviations used for each type? What does it mean for deafness to be syndromic or non-syndromic?
What types of gene products, when defective, are associated with deafness?

El-Amroui and Petit, 2005
This paper discusses five gene products that normally work together and that cause the same syndrome when individually defective. You should read this paper to get a sense of the general role of the proteins and how they interact with each other. Do not worry about all the transcripts and isoforms as discussed in the section right after the introduction. Also don't worry about the exact nature of the motifs within each gene product except for the interactions as shown in Fig 1.
Focus heavily on the figures as summaries for the text.
Skim the "Morphogenesis of the hair bundle" section.
Read more carefully the "mechanoelectrical transduction process" section.
Skim the "USH1 protein properties and interactions" and refer to Fig 1.
Relate the "USH1 proteins and the cohesion of the growing hair bundle" section to Fig 4. What kind of experimental techiniques underlie most of the information summarized here? How can experimants with mutant mice help researchers figure out relationships among the five proteins?
Skip the last part of the paper that discusses the retina. However, knowing that Usher patients have vision problems, why is it that particular mutations in these five genes can cause isolated deafness without other phenotypes? (See lower right paragraph of p 4594)

Bolz et al., 2001
What do all the symbols mean in Figure 1? What do the vertical lines between branches of the family represent?
How do the microsatellite markers indicate the mapping of the disease? Why has this family been assigned as USH1D and not USH1F?
How did the accompanying mouse study (DiPalma et al.) allow this study to proceed?
What is cadherin? Look up some outside sources to get an overview of function. Use Figure 4 to help explain the structure.
Find the supplementary data online that suggests expression of CDH23 in various tissues.
What's the general structure of the CDH23 cadherin?
Why is it relevant that the human protein is 94% identical to the mouse homolog?
How does Figure 2 relate to Figure 1? In Figure 2, how do the sequence traces and pedigrees relate to each other?
How does the nature of the mutations relate to the severity of the disease in different individuals?
Why do the authors say (in reference to the R1746Q allele) that "we cannot exclude the presence of another unidentified [pathogenic] mutation..." (p.110, left column)
In Figure 2j, how does the mutation lead to premature truncation of the protein? How can there be a stop codon in the middle of exon 36?
What is exon trapping? Look it up, and try to envision the logistics and data of the experiment described at the bottom of page 110, left column. (They don't show the actual data.)
How did studies of a German patient add to the conclusions of this paper? What is the nature of the mutations in this patient?

DiPalma et al., 2001 (questions from Bill and Brady)
1. Why are the authors trying to show that mutated Cdh23 gene in waltzer mice causes hearing loss?  What are the implications of this paper for studying deafness in humans? 
2.  What is a BAC contig?  Why is this approach useful here?
3.  What is STS content mapping?
4. What is the function of the organ of Corti?
5.      Consult Figure 2.  What is the mechanism by which each of the three mutant alleles (v^6J, v^Alb, v^2J) affects protein synthesis from the DNA level?  How are they different?  Why is there variety among the splice sites in 2g?
6.  Why might this otocadherin be expressed in many tissues?  Why is Figure 3e important?
7.  What are the differences between the wild-type and mutant stereocilia in Figure 4?

Connexin 26 items from 1998:
These three letters refer to a paper which we didn't read. What findings do you infer were made in the original Kelsell et al. paper? (In class we will see a couple of the Kelsell et al. figures.)
What is connexin? What are gap junctions? Why do you think gap junctions are important in the inner ear?
How can a gene potentially be connected with both an autosomal recessive and an autosomal form of deafness?
The Scott et al. letter reports findings that contradict the Kelsell et al paper. What's going on?
What did Denoyelle et al. find, and how does it fit with Kelsell et al and Scott et al?
What part of the protein does the mutation reported in Denoyelle et al affect?
How did White et al. (from Kelsell's group) do a functional test to test the effect of the controversial mutation?
How do we reconcile the M34T situation?