Usher syndrome, Part II: A complex molecular picture

Guest Blogger Danio:

I know, I know. Friday night isn’t exactly the best time to smack you with a big messy fistful of science, but PZ will be kicking us Minions out of the house early next week, so I have to stay on schedule with these Usher posts if I’m going to get through Part IV by the time he shows me the door.

In Part I, I introduced the hereditary disease known as Usher syndrome and went over a bit of the cell biology of auditory and visual sensory cells. In this post, I’ll discuss the molecules known to be affected in Usher patients, and begin to describe what is known about their function.

As mentioned previously, variations in the clinical presentation of Usher syndrome have resulted in the creation of three clinical subtypes. Type 1 is characterized by severe to profound congenital hearing loss, balance problems, and early onset vision loss, usually beginning before the patient’s 10th birthday. The type 2 hearing loss is also congenital, but tends to be less severe. The vision loss in type 2 usually begins to occur a bit later, in the early teen years, and these patients do not present with balance problems. All three categories of symptoms–vision, hearing, and balance, are progressive, commencing in childhood or adolescence rather than at birth, in Usher type 3 patients.

Despite these differences, the specific combination of deaf-blindness, plus or minus balance defects, led researchers to predict that multiple mutations in a single gene, or perhaps in two or three genes at the most, would turn out to be responsible for the symptoms observed in all Usher patients. The advent of genetic mapping led to surprising results in this regard. To date, at least 11 different genes have been implicated in the disease, nine of which have been molecularly identified thus far. More surprising still are the natures of the proteins encoded by the identified genes. In contrast to signaling or metabolic pathways, in which a genetic defect at any point in the regulatory chain of events will adversely affect the target and result in an abnormal phenotype, the Usher proteins do not act in stepwise fashion to regulate a cellular process. What they actually do is not entirely clear at this point, but the various proteins contain functional domains known to be important for scaffolding, cell adhesion and signaling, extracellular matrix formation, and motor activity.

Structural information about the Usher proteins provides a starting point from which researchers can begin to investigate their localization within the various regions of the sensory cells affected in Usher syndrome, their potential physical interactions with one another and, ultimately, the role of these proteins in sensory cell function and survival.

Antibodies against these proteins enable us to visualize their exact position within the cell, and such experiments show that most of the Usher proteins colocalize to the very structures that are involved in specific sensory cell function–the photoreceptor connecting cilium , the stereocilia of the mechanosensory hair cells, and the specialized, neurotransmitter-laden synapses of both cell types. Investigation of the various functional domains of these proteins has further shown that they can physically interact and bind to one another to form protein complexes.

So, what might this motley crew of proteins be doing hanging out together at these specific subcellular locations? The function of the Usher complex at the stereocilia has been relatively straightforward to address, particularly using mammalian models of the disease to examine the effects of depleting the function of any one Usher gene. In the first panel of the figure below, hair cells from the cochlea of a young mouse with no defective Usher genes are shown to have stereocilia that are nicely arranged in a crescent shape, and feature consistent length, width, and orientation. In contrast, the stereocilia of mice with mutated forms of Usher genes shown in the other panels are dramatically misshapen and disorganized.

figure from Brown, et al. 2008

The subcellular localizations of these proteins in hair cells, illustrated in the schematic drawing below, provide insights to how such disorganization might come about. Usher protein localization in the stereocilia is shown at three timepoints ranging from late embryonic to several weeks postnatal:

Figure from Brown, et al. 2008. (please note that the protein labeled “Vlgr1” is actually Gpr98 (Ush2C) using an older alias. Gene naming conventions can be a real pain in the ass sometimes :)

At the earliest time point, the Usher proteins fill the space between adjacent stereocilia, linking them from base to tip and thus providing maximum stability for the developing structures. During the early postnatal time points, these complexes continue to provide connections at the base and the tip regions of the stereocilia, with diminished contacts in the middle. Finally, the latest time point presents the configuration that will persist throughout the lifetime of the animal, in which only the tips of the stereocilia remain tethered together.

It’s important to note here that baby mice are born deaf and do not begin to hear until about the 6th postnatal day. The dynamic localization patterns of the Usher proteins in the schematic above serve to illustrate that, even after the mice are born, there is still quite a bit of fine-tuning going on both structurally and functionally with respect to the stereocilia. Human auditory development occurs on a different time scale (not surprising considering that mouse gestation is only 21 days long); fetuses can hear sounds in utero for several months prior to birth, but it’s likely that a similar process occurs in the growth and maturation of stereocilia in human hair cells prior to the 30th week of gestation.

Thus, noting that the presence of Usher proteins is required for normal growth and patterning of the stereocilia prior to birth, it is easy to understand why the hearing loss in patients with mutated copies of these Usher genes is congenital. These data also indicate that although the presence of Usher proteins at the hair cell synapse suggests a role in synaptic function, the primary cause of deafness, at least in Usher type 1 patients, is probably due to the perturbations of the stereocilia. These changes in stereocilia structure and function can also explain the balance defects associated with the type 1 and type 3 forms of the disesase, but it still isn’t clear why patients with mutations in any of the three Usher type 2 genes dodge this particular symptom.

Compared to the situation in the ear, the functional importance of Usher proteins in the retina is relatively poorly understood, but I’ll summarize the findings thus far in Part III, and then wrap up with some information about clinical diagnosis and treatment options in part IV.

Brown SDM, Hardisty-Hughes RE and Mburu P. 2008 Nature Reviews GeneticsVolume 9.


  1. Fernando Magyar says

    Yeah, well that’s great but where’s the Friday Cephalopod Pict? Seriously, that is fascinating stuff that I would never have had the opportunity to have heard about if it were not for your post on this subject. Thanks!

  2. JoJo says

    Thanks, Danio, for an interesting, well-written explanation of something I didn’t even know existed.

  3. Bob Spencer says

    Excellent, Danio. If this fascinating stuff continues, PaZazz can take his time in returning. So much more interesting than culture wars.

  4. MAJeff, OM says

    I’m trying to figure out a good way to phrase this. How are the types of Usher disease related to the geographic isolation/interbreeding issues you raised? Where, for instance, is type 1 more prevalent as opposed to type 3?

    (reminds me a bit of the higher prevalence of 5-alpha-reductase deficiency in parts of Greece/Turkey and the Dominican Republic)

  5. Danio says

    Thanks for the question, Jeff. The geographical isolation/interbreeding issue will be discussed a bit more thoroughly in part IV, but briefly if one or more of the ‘founders’ of these types of populations was a carrier for a mutation in a particular Usher gene, it would persist in the population and more people would wind up with two mutated genes and therefore exhibit Usher syndrome. For example The Acadian population in New Orleans (moved down from Canada a few hundred years ago and intermarried alot) has a high incidence of a particular mutation in the Usher syndrome type 1C gene. The Ashkenazi Jewish population is another high incidence group, for similar reasons, but involving a different mutated gene, and of course your 5-alpha-reductase deficiency is an example of the same phenomenon with a different gene.

  6. says

    Thank you for posting this. It’s quite interesting. I am thrilled you are taking the time to blog about such fascinating stuff. I really enjoyed reading the blogs you’ve posted.

    I have an off topic question though, Danio. We have situation brewing in Tulsa. It is a a clear violation of Church and State and I would like share the info with readers here in case anyone might be inclined to join us in a letter writing campaign. I have a great deal of respect for the people who frequent PZ blog, (Well, except for the cracker whackaloons who showed up). If any of your readers have the time and inclination, I would love it if they’d help us attempt to get through to the idiots in control of our local government. Who do I contact to ask if you would mind making a short blog about it?

    I created a post about it in our forum but I don’t think I should post the whole thing here. I’ll post the link in case anyone would like to join us in our complaint campaign. If posting the link is inappropriate, please accept my apology and delete it.

  7. SC says

    Now even if no one else reads it I’ll still be glad I took the time to post it.

    Just wanted to let you know that I’m reading, learning, looking forward to Parts III and IV. Thanks!

  8. Physicalist says

    We’re reading, learning, and enjoying . . . but it’s generally harder to make quips or generate controversy on the sciencey posts.

  9. Helioprogenus says

    Thanks for that well detailed explanation Danio. I jumped the gun on the last post because of all the molecular evo-devo questions, but you’ve done a great job explaining the molecular background. One thing I took from this however is the long road that’s still left to fully understand this condition/varian conditions. The link between these proteins and the retina is fascinating, and I wonder whether they have anything to do in stabilizing the eye cells in a given pattern of development. Considering the importance of the fovea, or the peripheral rod cells, perhaps some kind of cellular protein link early in development is at fault. Perhaps the cause of tunnel vision is linked to the uneven arrangement of the rod cells within the retina. Are there any theories as to what funcitonal changes occur to the proteins to effect vision?

  10. Danio says

    Great questions, all, Helioprogenus. I’ll answer some of them in the next post and gladly do some wild-assed handwaving about the remainder :)

  11. wright says

    Fascinating. My sister is an occupational therapist; through her and our mother (physical therapist, now retired) I’ve become curious about various forms of retardation, autism and genetic curve balls like Usher syndrome.

    Thanks for the lucid, unpatronizing explanations. I’m enjoying this series; keep up the good science writing!

    For what it’s worth, I’ll put in a good word with your Squidly Overlord. I commend his choice of minions :)

  12. says

    This is all way over my head, but you’ve managed to make sense of it to me. You do realize that writing lucidly about science at this level of expertise requires an apparently rare talent as well as care and work, right? Thanks for the work and hooray for the talent! This is a pleasure to read.

  13. LisaJ says

    Thanks for another fascinating post Danio. I am really enjoying your Usher syndrome series. The photos you show of the mutated sterocilia are awesome. It’s incredible to see with such detail how each of these related genes affects their structure differently. What a nicely written post. I’m looking forward to parts 3 and 4!

  14. Pat Silver says

    Thanks for some interesting science, Danio. It’s explained sufficiently clearly that someone like me who has some fairly basic scientific knowledge can follow it.