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All You Need To Know About The Usher Syndrome and Related Diseases Conference Part IV: New Genes and Common Denominators

October 7, 2010

By Jennifer Phillips, Ph.D.

Here I am again to do some of the heavy scientific lifting required for a subset of the talks presented at the Valencia meeting. Last time I covered the presentations dealing with the molecular and cellular activity of Usher proteins--the factors known to cause clinical Usher syndrome in humans when altered by changes in genetic code. To briefly summarize, there is strong experimental evidence to suggest that at least some of the time these Usher proteins physically link together to form molecular complexes that carry out some cellular functions. There are a lot of different Usher proteins involved, so understanding just the activities of those proteins has been quite challenging.

In the next series of talks, the picture gets even more complex, as we learn about still more proteins, contributing to other disorders of vision and/or hearing. Some of these may be added to the list of known Usher proteins, while others are associated with vision and hearing disorders distinct from Usher syndrome, but also appear to have molecular relationships to Usher syndrome proteins. If this sounds complicated, well, it is. But fear not, dear readers. I'm here to guide you through this confounding thicket of information, and I will do my best go easy on the technobabble whenever possible, link you to backup resources when I just can't help myself, and ferry you safely to the other side. Here we go:

Identification of a new Usher 3-like locus
Shzeena Dad, Kennedy Center, Glostrup, Denmark

This research described the discovery of a new gene causing Usher-like symptoms in a Dutch family. As the hearing loss is progressive in these family members, who also exhibit balance defects and retinal degeneration, the condition is is classified as most like Usher type 3. Two things convinced the researchers that it isn't Usher type 3a: The genetic change that the affected family members share is not in or near the Ush3a gene, or indeed, in any of the other eight known Usher genes. Moreover, all affected members of this family were born with cataracts-defects in the lenses of their eyes, which has not been reported in other Usher cases (some Usher patients do develop cataracts later in life, but this is the only family we know of who are born with this problem).

Why you care
One of the endearing realities about biology is that, however complex things might initially appear, they usually turn out to be even more complex than that. Studying Usher syndrome is already a formidable challenge, made more so because we know, with absolute certainty, that we have not yet identified all the molecular players. Obviously this is important, because despite the amazing progress we've made in being able to screen for mutations in Usher genes, we can only screen for the things we know to look for. Thus, the more new gene information we can generate, the more complete our picture will be, enhancing screening efforts as well as our ongoing searches for therapies. Adding this new locus to the list gives us another target to aim for.

New strategies/technologies to identify new genes
Hanno Bolz, Institute of Human Genetics, University Hospital of Cologne, Germany
Center for Human Genetics, Bioscientia, Ingleheim, Germany

This speaker described a several new screening strategies that could help cast a wider net for known Usher genes as well as new players. On the species level, there is a huge amount of variability in the human genome, so in the noise of all those normal, background genetic variations, small changes in genes that lead to disease can be hard to pick up. Traditionally, the most successful way to reduce the signal to noise ratio was to conduct genetic testing on large families, thus reducing the background level of genetic variation and making the important, disease-causing changes easier to spot. Happily, new technologies have delivered success in looking for disease genes even in small gene pools. New ways of searching, with better resolution for picking up the small changes, different techniques for finding a broader variety of changes, and better, faster sequencing so that vast amounts of genetic information can be collected in a very short period of time, are all working to our advantage. For example: deleted information in a particular region of a chromosome can be difficult to spot with traditional DNA sequencing methods if you're not specifically looking for it, but with a new technique called Comparative Genomic Hybridization such changes, and a number of other irregularities, can be detected without prior knowledge. This is useful not only for screening known Usher genes, but as a first step in changes in novel genes that might contribute to Usher syndrome as well.

In part III of the meeting summary, I explained how zebrafish are used as an animal model for Usher syndrome. In his talk, Dr. Bolz discussed a new way that zebrafish can contribute to the discovery of new Usher genes. Techniques that we use to disrupt gene function in zebrafish can be used to test whether a particular gene might be likely to contribute to Usher syndrome in humans. I humbly present one such example of this strategy here.

Why you care
In short, discovering new ways to examine the genes we know are involved in Usher syndrome as well as ways to identify new players is crucial to improving diagnosis and treatment.

Modifiers of ciliary diseases
Nicholas Katsanis, Duke University Medical Center, Durham, NC, USA

We've already discussed the putative role of the cilia in contributing to the symptoms of Usher syndrome. Cilia are important components in photoreceptors, hair cells of the inner ear, and many other cells of the body. Thus, it's not surprising that defects in these structures underlie a number of human diseases. These conditions have an extremely wide range of associated symptoms, which sometimes include, but are by no means limited to, hearing and vision defects. However, as the source of all these problems can be traced to problems with the cilia in some or all cells, they are classified collectively as "Ciliopathies" (diseases of the cilia).

Katsanis and colleagues have taken a systematic approach to studying factors classified as 'ciliary genes', using molecular screening techniques and animal models to characterize mutations in these genes and their potential disease causing effects.

Because a definitive link between the pathology of Usher syndrome and defects of the cilia is still being established, there is currently some debate about whether or not to include Usher syndrome on the official list of ciliopathies. The fact that many Usher proteins are known to colocalize in the region of the photoreceptor connecting cilium can be used to make a case for including Usher genes in this group. Another compelling argument for doing so is that we already know there is some level of molecular cross-talk between Usher proteins and other factors known to cause ciliary disease.

Why you care
The interactions between known Usher proteins is already pretty complex, but interactions also occur between Usher proteins and other, non-Usher proteins. Understanding more about how this works could enable us to identify new ciliary genes that may, in some circumstances, cause Usher syndrome, providing new targets for diagnosis through genetic screening and research for therapies.

The USH2A Interaction Partner NINL Associates With BBS6, Plays a Role in Establishing Planar Cell Polarity and Functions in Cilia Assembly
Erwin van Wijk, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

As much as I'd love to wax expansive on the particulars of this really exciting research, I'm starting to have that feeling I get at parties when I geek out over some neat bit of science in the news and chat excitedly about it for too long before it dawns on me that my conversational companion is surreptitiously making the 'SAVE ME!' sign to his or her partner across the room. So, let's do a very rough sketch of the basics based on the informative title of this talk, and call it a day:

The USH2A Interaction partner NINL: USH2A is the gene behind Usher Syndrome Type 2A. It encodes a very large protein called either USH2A or Usherin. It's a common biochemistry research tactic to use all or part of a known protein and find other proteins that can physically interact with it. These researchers used a portion of the Usherin protein as their 'bait' to fish through a solution containing many proteins to see what would stick to it. One of the proteins they discovered was an already characterized factor called NINL.

NINL associates with BBS6: As soon as the researchers determined that NINL interacted with Usher syndrome, they wanted to figure out what the effect of a mutation or other disruption of NINL might be. So, they depleted NINL in a young developing zebrafish (using the same technique of disrupting zebrafish gene function discussed above). These animals had developmental defects that were reminiscent of the defects seem when genes involved in Bardet-Biedl Syndrome (BBS) are disrupted in zebrafish. BBS has a number of genes associated with it, is officially classified as a ciliopathy, and has symptoms that include progressive retinal degeneration. The researchers continued to investigate the consequence of depleting NINL in tandem with members of the BBS gene family, and observed genetic interactions between NINL and many of the BBS genes. They then conducted the same type of protein interaction experiment as was used to identify NINL as an USH2A interaction partner, only this time they used NINL as the bait. Through this experiment, they were able to show a direct physical interaction between NINL and one of the BBS proteins, BBS6.

NINL plays a role in establishing planar cell polarity: In a nutshell, planar cell polarity refers to the organization of cells that make up a given tissue or organ. During development, the cells have to coordinate their growth and movement to form eyes, ears, kidneys, brains, etc. Determining which end of the cell is 'up' is an essential part of this organization, and it is known that the cilia of cells contribute to this organization. Thus, it is hardly surprising to note that mutations in genes known to be important for ciliary development or function can lead to disrupted cell polarity. This is true of the BBS genes, and in this study, the researchers noted disrupted cell polarity in zebrafish with reduced NINL gene function.

NINL functions in cilia assembly: The evidence from zebrafish, as well as what was already known about the localization of NINL protein, was suggestive that NINL might have some role in cilia formation or function. To establish this more directly, the researchers conducted an experiment with ciliated cells in culture dishes. They depleted NINL function in these cultured cells and observed a defect in cilia formation. This added data makes it even more likely that the problems seen in the zebrafish model are the result of poorly assembled cilia.

Why you care
Essentially, this is proof of principle for the approach that Hanno Bolz, Nicholas Katsanis and many others are advocating on a wider scale: Look for connections between known and potential contributors to Usher syndrome, or to cilia formation and function. Use genetic and biochemical tools to identify new molecular players, use model organisms to study the effects of disrupting these factors alone or in combination with other known contributors. Fill in the gaps and refine the definitions of these disorders by revealing how they relate to one another.

I see you giving the high sign to your spouse over there, so I'll let you off the hook for today, and I thank you for indulging me. Next time, Mark will be back to conclude this meeting summary with some information about new genetic screening techniques for Usher syndrome. Until then, be well!

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