In Part I I gave a rough overview of Usher syndrome and went over a bit of cell physiology of auditory and visual sensory cells. In this post, I’ll introduce 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. Although the vision loss in type 2 can become as severe over time as that seen in Type 1 patients, the first symptoms usually begin to occur a bit later, in the early teen years. Finally, these patients do not present with balance problems. In Type 3 patients, all three categories of symptoms—vision, hearing, and balance, are progressive, with even the hearing loss commencing in childhood or adolescence rather than at birth.
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. This is the case, for example, with Cystic Fibrosis. Just like Usher syndrome, CF is a recessive disease, meaning that you need two defective copies of the gene to show the disease symptoms. Importantly, even though there is a remarkable degree of variation in symptom severity, the vast majority of CF cases are due to mutations in only one (albeit extremely large) gene.
With respect to Usher syndrome, the advent of genetic mapping led to surprising results in pinpointing the genetic underpinnings of the disease. To date, at least 11 different genes have been implicated in USH, nine of which have been molecularly identified thus far. More surprising still is the wide variety of proteins encoded by the identified genes. In contrast to standard signaling or metabolic pathways, in which a genetic defect at any point in a linear chain of events will result in the same basic problem downstream, the Usher proteins do not appear to act in stepwise fashion to regulate a cellular process. What they actually do, in fact is not entirely clear, but the various proteins contain functional domains known to be important for:
- scaffolding: providing a structure on which multiple proteins can convene to assemble into a complex.
- cell adhesion: spanning the minute distances between a cell and its neighbor.
- signaling: molecular chitchat between cells in the same neighborhood.
- extracellular matrix components: proteins that confer structural support to the regions around cells.
- motor activity: the job of transferring molecules from where they’re made to where they’re going to work in the cell.
So, what might this motley crew of proteins be doing hanging out together at these very specific subcellular locations? The function of the Usher complex at the stereocilia has been fairly well studied using mouse or rat 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 rows of stereocilia that are nicely arranged in a crescent shape, as well as consistent length, width, and orientation of the individual stereocilia. In contrast, the stereocilia of mice with mutated forms of Usher genes (all Type 1 genes in this case) are dramatically misshapen and disorganized.
Thus, noting that the presence of Usher proteins is required for normal growth and patterning of the stereocilia prior to the acquisition of hearing, 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 Usher proteins may also play a role at the hair cell synapses, based on their expression there, 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 disease, 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.