Usher syndrome, part III: the plot thickens

Guest Blogger Danio:

The time has come to delve into the retinal component of Usher syndrome. In Part II, I briefly described the results of protein localization studies, in which most members of the Usher cohort were found at the connecting cilium of the photoreceptor and at the photoreceptor synapse. The following diagram summarizes these findings:

Usher protein localization in photoreceptor cells. From Reiners, et al. 2006

So, as we saw in the ear, proteins with the equipment for physically interacting with one another are gathering in specific places, and thus multi-protein complexes are likely being formed at these locations. The cluster of Usher proteins around the connecting cilium has been the focus of most of the current retinal studies, and to understand the potential importance of an Usher complex at that subcellular location we must address the importance of the connecting cilium itself.

Recall the structure of the photoreceptor cell described in Part I. The inner segment, just above the nucleus, contains all the standard-issue cell operating equipment–organelles required for producing protein, degrading cellular waste products and performing various other metabolic functions. The outer segment contains the intricately folded membrane discs with which light sensitive molecules are associated. Between these two cellular compartments lies the connecting cilium, which grows out of the inner segment, extends up into the outer segment, and is surrounded by a structure known as the periciliary ridge, which encircles the cilium like a little cuff. The cilium serves as a functional connection between the inner and outer segments, as well as a structural one. Proteins and other cellular materials synthesized in the inner segment need to get to the outer segment in order to perform their particular jobs up there, and materials that are no longer needed in the outer segment need to be carried away and dealt with in the inner segment. The connecting cilium acts as a transport system to which motor proteins can anchor and pull their molecular cargo up or down as needed.

The localization studies of the Usher proteins reveal that they are in the vicinity of the connecting cilium, but a closer look at this region of the cell shows that they are specifically either in the periciliary ridge–the ‘cuff’–or the space between the periciliary ridge and the connecting cilium:

Schematic longitudinal (B) and cross (C) sections of the ciliary/periciliary region of a mammalian photoreceptor cell showing the localization and proposed activity of some interacting Usher proteins. From Märker, et al. 2008

Thus, the model for usher protein function in the retina is that these complexes somehow assist in the cilium-based transport system. Here’s where things get a bit murky, though. Remember that, unlike the congenital nature of the ear problems, the retinal symptoms don’t manifest until much later, in childhood or adolescence,. Furthermore, they progress quite slowly, well into the third decade of life in most cases. How can the same defective proteins that cause such significant developmental problems in the hair cells not cause early problems with retinal cell function as well?

The congenital deafness in human patients and mouse models of the disease, and the defects in stereocilia formation seen in the Usher mice are nicely explained by the model of protein interaction and function in the developing hair cells, discussed in Part II. The retinal cells, however, survive development and, apparently, function normally until they begin to degenerate. I say ‘apparently’ because the ‘pre-death’ state of the photoreceptors has been difficult to observe thus far. In human patients, the first sign of a problem occurs when the hearing-impaired child or teenager begins to experience night blindness due to a loss of rod photoreceptors in the periphery of the eye. By the time this can be detected clinically, the degeneration is already well underway, and although the progressive vision loss is gradual, ophthalmic examinations haven’t yet been able to identify any problems that precede the cell death.

At this point you might well ask what clues the Usher mice, which proved so valuable in adding to our understanding of the disease progression in the ear, can tell us about the events leading up to retinal degeneration. To our great consternation, most of the Usher mice do not undergo retinal degeneration at all! The Usher mutant lines have all been examined expectantly until the end of their natural lives (around 2 years) and most do not exhibit any abnormality in their retinas. The exceptions to this are older mice with mutations in the cadherin 23 (ush1d) gene, which show a slight reduction in visual function older ages, and myo7a mutant mice, which exhibit a fairly distinct defect in protein trafficking, lending support to the model of usher proteins at the connecting cilium as described above. Neither line shows any retinal degeneration, however.

Several theories have been put forth to explain this discrepancy between the mouse and human forms of the disease. One possibility is that mice, being nocturnal animals and usually raised in low-light laboratory conditions, may not endure the bright light exposure that human retinas must withstand. Another explanation may lie in the slow, progressive nature of the human disease and the relatively short life cycle of the mouse–perhaps two years just isn’t long enough for the retinal defects to manifest in the mouse retina. A third theory centers on the fact that all of the known Usher proteins actually exist in multiple isoforms. The genetic code that specifies each of these proteins can be cut and spliced in a few different ways. The exact roles of the different isoforms of every gene aren’t yet clear, but some of them do appear to be more important in the ear than in the eye. It’s possible that the mutations in mouse Usher genes that give rise to such a strong ear phenotypes don’t affect the part of the protein that’s important for retinal cell function, and thus the mouse is spared the vision loss that characterizes the human disease. In further support of this latter theory is that fact that many of the Usher syndrome genes are also linked to non-syndromic deafness in humans–hearing loss without associated blindness.

None of the above theories are mutually exclusive, and it may turn out to be a combination of genetics, environment and life-span that has limited the retinal phenotype of the Usher mutant mice. Encouragingly, significant progress has been made through the use of genetically engineered mice, in which an Usher protein is removed completely (see knockout mice for more on this technique) or, alternatively, a targeted mutation is introduced into a particular Usher gene that renders the encoded protein non-functional. Thus far, these genetically modified mice show late-onset retinal degeneration, usually detectable at around 20 months of age. Exhibiting the full range of Usher syndrome symptoms, these new mouse models will provide hitherto unavailable opportunities for exploring the still mysterious function of the Usher proteins in the retina.

Hopefully, the above summary has illustrated that there are still a great many unanswered questions surrounding the pathophysiology of Usher syndrome, particularly with respect to the timing and progression of the retinal defects. To complement the data being collected from the current mouse models, I have chosen to investigate the function of various Usher proteins in the zebrafish. There are some differences in the retinal anatomy of zebrafish and humans, but basic cell structure and function is conserved between the two species. Additionally, there are some similarities that make zebrafish an especially appealing organism for this type of study, including the fact that fish are diurnal animals with rich color vision–even better than humans, in fact, as they can see light in the ultraviolet range of the spectrum. Other advantages to using zebrafish are related to their development. Zebrafish embryos undergo fertilization and development outside the mother’s body, and usually several hundred embryos are produced from a single mating. They develop rapidly and are able to swim, see and hear just a few days after fertilization. Thus, I am able to begin conducting tests on their visual function within the first week of development and obtain results quite rapidly compared to the work being done in mammals.

I am in the process of making Usher mutant zebrafish lines using a new technique for targeted mutagenesis. In the meantime, I am able to use established techniques to study the consequences of depleting Usher proteins in larval zebrafish. Although most of these data have yet to be published, I can report that, along with balance and hearing defects, I am seeing problems with retinal cell function, and I am able to detect photoreceptor death in young fish in which the various Usher proteins have been disabled. Once the starting point of the cell death is pinned down for each of the genes, I examine various aspects of retinal cell structure and function prior to that time point to see if I can detect any abnormalities. Manuscripts are in preparation, so stay tuned.

Understanding the molecular events that precede the death of these cells will be crucial in identifying ways to improve diagnosis and treatment of Usher syndrome. In the conclusion of the Usher story, and of my Guest Blogging stint, I’ll discuss current clinical practices for managing Usher syndrome, and the direction of the research efforts designed to enhance these treatments.

Figure credits: 1. Reiners J, et al. 2006Experimental Eye Research Volume 83, 97-119.
2. Märker T, et al. 2008 Human Molecular Genetics Volume 18, 71-86


  1. JohnnieCanuck, FCD says

    So much detail in such a small area of our genome. No chance of running out of new material to explore, for years to come, at this rate.

    So many wonders, yet to be found.

  2. Louise Van Court says

    Danio may your research prove fruitful in tracking down the mysteries yet to be solved about the exact cause of the degeneration of the photoreceptor cells in Usher syndrome. Thanks for describing the present state of the research so that lay people can get a bit of an idea of what you do.

  3. says

    Guys, sorry, this is OT, but we have another poll to crash. Right now on Do you believe God’s intervention could save a family member even if doctors say treatment would be futile? Seriously. At the time of this post, it’s 60/40 in favor of “yes.” People are sad.

  4. Bryce says right now…stupid poll about god healing people when medicine can’t. Rally the troops!

  5. Helioprogenus says

    Thanks for the thorough analysis Danio. You’re really good at keeping us on our toes as far as waiting for the next post to further illuminate us on Usher’s Syndrome. As any amazing writer does, you purposely leave some gaps and mysteries which keeps us begging for more. I wish you great success on your research, and just as I was thinking what other animals besides mice could they use for the research into the retinal proteins, we find out you’re working with Zebra fish. As far as the mice studies, they are working on artificially extending the lives of mice even further, so perhaps when they’re able to do that, we can see what kind of retinal degradation they suffer in their advanced age.

  6. Helioprogenus says

    What are you talking about Randy? You feel like every single thread needs to be specifically about a scientific topic? I thought PZ already addressed that before, but in case you didn’t hear, or are somehow extremely forgetful, if you’re not satisfied with the science on this blog, go find another one that satisfies your needs. Why waste your pathetic life commenting on another blog that is doing quite well without your input. Perhaps if you’re so driven, you can get an advanced degree in any scientific field of your choosing, and blog only about that.

  7. Reginald Selkirk says

    Thank you for a very educational post. I used to believe that “usher syndrome” was brain damage which displayed itself through symptoms including counting up the begats in the Bible to calculate the age of the Earth and the timing of the Apocalypse.

  8. says

    Danio- outstanding write ups- very clear and up to date scientifically. Keep up the good work and amongst you and all your lab mates, hopefully we’ll find preventions and treatments for Ushers.

    All the best
    steve rose

  9. Danio says

    Randy, you’ve commented vapidly on two of the three Usher posts thus far. If you’ve interpreted the molecular trail of breadcrumbs I’ve left in these posts as evidence for ‘design’, so be it. But tell me, please, how does the progressive blindness of an already deaf person who relies exclusively on visual means of communication and interaction with the world suggest any sort of ‘intelligence’ to you?

    Seriously, I’d like to know how you spin this.

  10. Helioprogenus says

    I came accross an article on live science that you might find interesting as far as how “the human visual system processes sound and helps us see”.

    I wonder if Usher’s would also involve deficits in these cross system reinforcing processes.

    I’m sure they’ll have to do plenty of work in terms of the molecular structure of these “bi-sensory” cells, but I’m willing to bet there might be some Usher proteins involved.

  11. Helioprogenus says

    Oops, I meant Usher’s-related

    As for Randy, let me reiterate that you have absolutely nothing to contribute thanks to your indoctrinated and irrational thinking. Why don’t you be honest with yourself, dump the intelligent design moniker, and admit to everyone here as to what you are. A petty little moron who believes in some kind of imaginary nonsense that in no way contributes to anything progressive in society. If you want to maintain your ignorance after all of this, feel free, but don’t waste your time typing away your stupidity anymore.

  12. Danio says

    It is an interesting finding, indeed, but all of the sensory processing they’re discussing actually happens in the brain, rather than the sensory organs that are directly impacted by Usher syndrome.

    Cool experiment, though, as it does suggest that there is more interplay and plasticity in the sensory cortices of the brain than previously thought. Here’s another older, but still cool study investigating this plasticity:

  13. Nerd of Redhead says

    That was a clear explanation. I can’t wait for the final installment(s).

  14. LisaJ says

    This is great stuff Danio. I just wanted to say that I’m really enjoying your Usher syndrome series, and am eagerly awaiting your last installment!

  15. Louise Van Court says

    Danio I was just reading about this paper at Science Daily and was wondering if it will have any bearing on your research? The mention of the “defective cilia” and “retinal degeneration” makes me wonder. I am sure each discovery helps move the research further along.
    Journal reference:
    1. Tsang et al. CP110 Suppresses Primary Cilia Formation through Its Interaction with CEP290, a Protein Deficient in Human Ciliary Disease. Developmental Cell, 2008; 15 (2): 187 DOI: 10.1016/j.devcel.2008.07.004

    “We are trying to understand the regulation of processes that are fundamental to normal cell development and health in humans,” said William Y. Tsang, Ph.D., of the NYU School of Medicine and Cancer Institute, and first author of the paper. “Defective cilia are implicated in a wide range of serious illnesses such as polycystic kidney disease, retinal degeneration, and neurological disorders. Inappropriate activation of signaling molecules that normally reside at the primary cilium, may lead to certain cancers.”

  16. Danio says

    Thanks for mentioning this, Louise. Turns out that there are a number of human diseases caused by defects in ciliated cells, and as sensory cells definitely fall into this category, blindness and deafness can be a part of a whole suite of symptoms (see, for example, Bardet-Biedl syndrome or Leber’s Congenital Amaurosis).

    The ciliopathy discussed in the Dev Cell report you mentioned appears to be caused by a defect in cilia formation, in contrast to Usher syndrome (and BBS), where the cilia forms just fine, but the molecules that regulate ciliary function– as a conveyer belt between regions of the cell– are messed up.

    Learning more about the cilia in general is very helpful for the big picture, so thanks much for your comment.

  17. says

    Hi Danio. You said

    But tell me, please, how does the progressive blindness of an already deaf person who relies exclusively on visual means of communication and interaction with the world suggest any sort of ‘intelligence’ to you?

    Things which are designed always have or develop flaws. I drive a Prius which is a fairly state of the are car. Eventually it will break down and stop running. Does that mean the engineers that designed the car are stupid or don’t exist?

    If I scratch myself, I bleed, a scab forms, underneath tissue repair occurs, the scab fall off and I am like new. From an engineering perspective that’s pretty impressive. If only my Prius could do that.

    Your question could be considered a variation of the problem of evil and that has been significantly debated by those who have thought about it more deeply than I. My answer to that problem goes something like this. “Maybe God isn’t what you think God is”.

  18. Sili says

    Fish have ears?!

    More seriously, thank you for a great summary of a complicated subject.

    Just goes to show why I’m not as sciencey as I’d like. I was sure the late onset was the reason for it not showing up in mice. In fact as I read, I was hypothesising that the cause could be the slow build-up of some sort of byproduct that eventually clog up the works – or poisons the cell – in sufficiently large amounts.

    Obviously wrong when reading the rest of the post.

    But tell me, please, how does the progressive blindness of an already deaf person who relies exclusively on visual means of communication and interaction with the world suggest any sort of ‘intelligence’ to you?

    SIN! Duh!