Dispatches from ARVO 2014, Day 3: It's all about you

May 7, 2014

by Jennifer Phillips, Ph.D.

Another great day of talks and poster presentations has concluded. Since I’ve spent the past few days talking in generalities, I’ll spend today’s blog giving a brief overview on the research specifically dealing with Usher syndrome.

Ieva Sliesoraityte is a clinician scientist who is part of the Eur-USH network of young investigators studying Usher syndrome in Europe. Last fall, Eur-USH initiated a study that aims to obtain visual function tests and genetic information from as many Usher patients as possible. Their goals are to develop a high quality, standardized clinical method for diagnosing and tracking USH, and to develop and maintain a database with genetic and clinical testing information so that patients can readily be identified for clinical trials in the future. Dr. Sliesoraityte, together with Dr. Jose-Alain Sahel and their team of researchers, use state of the art ophthalmic imaging techniques to characterize how the retinas of USH patients look at various stages of the disease. So far, they appear to have good solid trends on the visual function in for USH2 (all patients in the studies they showed were USH2A) and USH1 (all but one patient was USH1B). They also presented a nice, non-invasive test for determining how many cone photoreceptors were still functioning based on observing the dilation or constriction of the pupil in response to light of a certain wavelength. This response was measurable even in patients with a flatline ERG. The hope is that with enough data of this sort, researchers will be able to identify trends and critical points in the progression of the disease that would need to be considered when interventions become available. This last test, for example, provides a sensitive indicator of cell function that is not picked up by standard ERG techniques.

Only three USH3 patients have been through the testing so far. All three were in their early to mid 20s, which is a fortuitously narrow age range. However, each of the three had very different levels of visual function. USH3 is well known for its variable clinical presentation, and even this small sample size suggests that spotting trends with such a broad range of symptoms will probably be challenging.

Yuri Sergeev, a staff scientist at the National Eye Institute, had an interesting poster analyzing the protein structure of Usherin. As many of you know, Usherin, the protein encoded by the USH2A gene, is enormous. Understanding how it works has been a challenging task for molecular biologists and biochemists. When we evaluate mutations, we’re tying to anticipate how changes in the DNA will affect the shape or function of the corresponding protein. Mutations that erroneously encode a premature signal to stop making the protein are almost always disease-causing, and thus newly discovered mutations fitting that description can be categorized as pathogenic with a fair bit of confidence. Many mutations don’t cause an early stop, though, but instead alter the code so just one of the protein building blocks, called amino acids is swapped out for another. Sometimes the affected amino acid is known to be crucial for some important molecular interaction, and in that case it’s easy to imagine how losing that function could lead to disease, but many amino acid substitutions don’t fit that description.

Amino acid sequences are often represented linearly, like beads on a string. In real life, however, functional proteins seldom look linear. Instead, they are folded and wadded and wrapped around themselves. This folding doesn’t happen randomly, but is specified by the relative affinity that the amino acids have for one another. Some amino acids attract each other and form physical connections, bringing two parts of the bead-string close together. Other times they repel one another so that the parts of the folded protein where these opposing amino acids reside are far apart. The shape of the protein is important for its function—it’s not just about having the full length of the molecule encoded, but a code that is correct enough to fold in the right way. If a protein folds incorrectly, our cells have a pretty effective detection system for taking it out of circulation. This recognition system is based on the cell’s ability to detect parts of the protein that are normally tucked inside the properly folded structure, but, due to misfolding, are now poking out into the cellular environment. Think of it like a quality control team, inspecting t-shirts as they come off the assembly line and pitching the ones that have the tag sewn on the outside of the collar instead of the inside.

Using a combination of computer protein modeling methods, Dr. Sergeev analyzed a collection of mutations identified in USH2A patients that caused single amino acid substitutions. He analyzed the predicted overall shape change, changes to functional domains known to be important in Usherin function, and also whether the predicted shape change caused by the substitution would expose some of those ‘t-shirt tags’ and attract the attention of the cell’s quality control department. This research adds an important tool for scientists tracking which of the numerous mutations present in every human genome might contribute to disease.

Also in USH2A news, Katsuhiro Hosono and colleagues reported on identifying several mutations in Japanese patients diagnosed with Usher syndrome. These particular mutations have never been reported in any patients with European ancestry.

Finally, there was a report by a Samer Khateb, part of a research group in Israel, on a study that was published just days before the start of this meeting. This study described cases of Usher syndrome in a family that appear to be caused by a combination of two genes not previously linked to Usher syndrome. One of these genes, C2ORF71, was previously known to cause nonsyndromic RP, but the other, a gene called CEP250 hasn’t been linked to any human disease. Interestingly, there were two different manifestations of Usher within this family. Family members who had two mutated copies of CEP250, in combination with one mutated copy and one normal copy of C2ORF71, had early onset hearing loss and relatively mild RP by USH standards. Family members who had two mutated copies of both CEP250 and C2ORF71 also had hearing loss, but with early onset RP that was more severe than the nonsyndromic RP caused by mutations in C2ORF71 alone.

One take home message from today’s report is that, although there is obviously much more to learn about both the genetics and the clinical presentation of USH, we have new information to add to our collective efforts thanks to these researchers. I hope you can also see that none of this work would have been possible without the voluntary participation of Usher patients around the world. We need your help to understand the genetic cause of your disease. We need to collect this information so that it will be available for researchers to study how Usher proteins are affected by changes in the DNA code, or to correlate a certain set of visual symptoms with a particular genetic mutation, or, someday, to determine which patients are best suited for a clinical trial. If you haven’t already done so, please consider adding your information to the Usher Syndrome Registry.

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