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Monday, August 22, 2011

Seeing Things

by Mark Dunning

“I like having Usher syndrome because I have gotten to see a lot of things.” – Bella Dunning

The first place I thought of was Monterrey. The wildlife is so close there and Bella loves animals. Harbor seals sleep on the beaches, the dark pupils of their eyes visible when they blink out of the sea and flop, flop, flop ashore. Sea lions argue and wrestle like siblings on the breakwaters or bark unpleasantries at the fishermen that chase them from boat decks with hoses. The mats of kelp sit heavy on the swells just off the pier and are home to families of comical otters waving and rolling, scratching and napping.

The sky is gray in August, the mist cold and fresh. The canneries are gone replaced by colorful shops all tossed on top of one another, the usual tourist fare; chocolates and ice cream, “I’m with Stupid” t-shirts, Bubba Gump Shrimp restaurant and gift shop. Brown signs praise Steinbeck and eulogize the way things were; black cars with bald tires, tired men with cigarettes in their mouths, piles of fish still silver even in black and white photos. The aquarium sits unassuming at the end of cannery row. Inside it’s an ode to what is outside with otters and thin legged birds and blue fine tuna and sardines and sardines and sardines.

Take the Pacific Coast highway from the south. The vistas are beyond words. Thousand foot drops to the steel gray Pacific below, a rickety fence all that stands between fender and oblivion. The road crumbles in hairpins and drops and climbs up, up, up, until the ocean mist melts in to the clouds. Knuckles turn white on the steering wheel. Kids unconsciously slide toward the middle of the seat, away from the windows and the door that might accidentally flip open. Everyone giggles and gasps in awe. It has to be seen to be understood.

That’s why I thought of Monterrey when we first got Bella’s diagnosis. I thought she’d never see it. It’s a long way from the east coast where we live. It’s too far. It costs too much. I hadn’t been there in fourteen years and Bella probably never would be. She’d never see it and it had to be seen to be understood.

At the Usher Syndrome Family Conference in July, Bella sat on a panel and answered questions for the audience about what it was like to have Usher syndrome. At 12, she was the youngest of the panelists. When she was asked her thoughts about having Usher syndrome, she answered, to my amazement, that she liked having Usher syndrome ‘because I have gotten to see a lot of things.’

Now it was true that we had gone to Iowa via Chicago to visit Drs. Stone and Kimberling. We had also driven to Philadelphia to see Dr. Jacobson. And the Usher Syndrome Family Conference was in Seattle last year, so we took it as a vacation and went to Vancouver, too (long before my Bruins won the Stanley Cup there and set off riots). But I think Bella meant more than that. She meant she’d seen the leaves change in the fall and the snow piled three feet high and the hummingbird that likes to visit our daylilies. She’d seen me trying to coax another circuit around the lawn out of our lawnmower (it didn’t make it) and seen her two year old nephew bright pink with popsicle drippings. It’s something she’s learned from having me nudge her to watch life closely, to pay attention to things she might never see again. I’m no sage. I’m just a dad terrified his daughter might lose her sight. But Usher syndrome has taught her well.

See things while you can and enjoy them. You never know when you’ll see them again.

A couple of weeks ago I had to travel for business. San Francisco one week, Los Angeles the next. I took the family with me. Over the weekend we drove down the Pacific Coast Highway to Monterrey. Bella saw the aquarium, the wildlife, the vistas. She spent hours glued to the window of the car or the rail of a pier. I stayed on her shoulder, gently reminding her that she may never be back and she should be sure to take it all in.

She reminded me to do the same.

Friday, August 12, 2011

Usher syndrome, Part II: a complex molecular picture

by Jennifer Phillips, Ph.D.

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.
  • membrane integration: a protein that inserts itself into the membrane of a cell, sometimes weaving in and out multiple times. Transmembrane proteins perform a wide variety of functions, so this characteristic alone tell us only where to find it, not what it’s doing.
    Table of the known Usher genes and protein identities.
Structural information about the Usher proteins provide a starting point from which researchers can begin to investigate their localization within the various working parts 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 to 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. Laboratory experiments with the various functional domains of these proteins have further shown that they have the ability to physically interact and bind to one another to form a protein complex.

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. 

from Brown et al, 2008. The top left panel shows an electron micrograph of a normal, healthy mouse cochlea. Above each additional panel, showing cochleae from Usher mice, is the name of the mutant line, chosen based on the observed behavior. Because of the balance problems, these mice tend to run in circles and toss their heads. The affected gene in each case is listed below the name.
The subcellular localization of Usher 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 are shown at three timepoints ranging from late embryonic to several weeks postnatal.  
From Brown et al, 2008. This is a cartoon of highly magnified stereocilia, just showing the relationship between two neighboring stereocilia projecting from the same hair cell. Each little colored shape represents an Usher protein or a known interacting protein. Three different developmental time points are shown, from left to right. The stereocilia on the far left represents a time spanning from late gestation to newborn, followed by representations of two additional postnatal time periods. Note that the location of and relationships between the little colored shapes changes quite a bit over the course of this two week period.
 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 of the Usher proteins in the schematic above, in which many of them appear to move from one part of the stereocilia to another over time, serves to illustrate that even after birth there is still quite a bit of fine-tuning going on both structurally and functionally with respect to the stereocilia in the mouse. Human auditory development occurs on a different time scale (not surprising considering that mouse gestation only takes 21 days versus 40 weeks in humans); 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 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.

Monday, August 1, 2011

The Only Certainty

by Mark Dunning

Forever is composed of nows. ~Emily Dickinson

I have a friend with Usher syndrome. She worries about it. I know she does. I can see it in the way her eyes brighten when we talk about potential treatments. I can feel it in her enthusiasm for knowledge about the disease. Yet she does not live like someone who worries about Usher syndrome. She stubbornly refuses to let the future decide her present. She lives for today.

She has long been my hope for my daughter’s future. When she was young she drove thousands of miles with a vanload of friends to exotic locales, scraping by, sleeping on floors and in hostels. She lived crazy, carefree. She got her nose pierced. When she was older she fell in love, got married, had children. She travelled for her career then, dressed stylishly, pulled a rollerboard and used a smartphone. But she still has that same young smile, she still has her nose pierced. She has always been alive. That’s the best description of her. Alive. I want my daughter to be that way. I want Bella to be alive.
I am training to run a half marathon. I ran ten miles this past weekend and when I finished, I felt more like a corpse than an athlete. I have never been a runner before. Just read this if you don’t believe me. The irony is that I have taken up running to escape death, rather than court it.

When Bella was diagnosed with Usher syndrome, I found myself laying on the floor in the dark, my mind racing uncontrollably into the future. In a blur she was giving up horse riding, struggling in school. Then she was out of work, living in a sterile apartment. Then she was grey haired with a cane sitting at a family outing oblivious as her brother’s kids scurried around her. Then, just like that, she was dead.

Wait a minute. She was dead? That’s it? Four sentences then dead? The diagnosis had turned out to be far more dire than I ever imagined. It was even worse when I put myself in the story. If Bella was grey haired at her brother’s party, where was I? Gulp.

I put down the Ring Dings and took up running. I did it so I could be alive to help Bella. I wanted to be there to help her find a way to keep riding horses. I wanted to kick her out of the house to go to parties and socialize and make friends. I wanted to embarrass her when she felt sorry for herself and make her go to college even if she didn’t want to. And I wanted to be at that party to see grey haired Bella smiling as her children played with her nieces and nephews.

More than anything I swore to do my best to live in the present. That is where I am content. In the present Bella can see and in the present I am alive.

People with Usher syndrome are not miserable. They are not unhappy. Oh sure, they might get frustrated with their condition from time to time, but I don’t think they curse their fortune any more than, say, the average middle-manager cubicle jockey. The distinction lies in the future. The cubicle jockey envisions a brighter future in the corner office while people with Usher tend to fear the future. They dread a darker tomorrow.

The truth is, though, that we all face a darker tomorrow. If we look too far in to the future, we’ll find that we’re all dead. Sorry, but it’s true. A thousand years from now we’ll all be dirt.  But none of us look THAT far in to the future. To think a thousand years ahead would cripple all of us. We couldn’t function. We are much better served living today, trying to improve tomorrow, and not thinking about the distant future.

I often wonder why we families with Usher struggle so hard to take that same approach to the disease.  It’s not like we are unfamiliar with the process.  We all ignore the future to some degree.  Today, we are happy and functioning.  Do we really need to concern ourselves with more than that?  As Albert Einstein once said “Never think of the future. It comes soon enough.”

My friend inspired me to write this post. She always inspires me. She was recently diagnosed with cancer. I don’t write this as a eulogy for her, but I am very worried about her. I know it is constantly on her mind. I know she sees it in the mirror in the morning, in the eyes of her husband, in the faces of her children.

This is a painful irony. She has spent her life refusing to believe she would lose her vision. Now that might be true, but for the all the wrong reasons. I want Usher syndrome to be prominent in her life once more. I wish more than anything that it could be the reason she enjoys today. She has always been alive, thriving in the present. I wish she could stay that way forever. She is my hero. I want my daughter to be just like her.

I want her to be alive.

EDITOR'S NOTE.  My friend passed away a few weeks ago.  She never lost her vision to Usher syndrome.  Somehow that doesn't seem to matter at all.