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.