Navigation Links
In retinal disease, sight may depend on second sites

If two people have the same genetic disease, why would one person go blind in childhood but the other later in life or not at all? For a group of genetic diseases so-called ciliary diseases that include Bardet-Biedl syndrome, Meckel-Gruber syndrome, and Joubert syndrome the answer lies in one gene that is already linked to two of these diseases and also seems to increase the risk of progressive blindness in patients with other ciliary diseases. The findings are published online this week at Nature Genetics.

We are limited in our ability to predict how seriously a genetic disease will affect individual people, even when changes in specific genes have been identified and tied to particular diseases, says Nicolas Katsanis, Ph.D., an associate professor of ophthalmology and molecular biology and genetics at the Johns Hopkins School of Medicine McKusick-Nathans Institute of Genetic Medicine. "In the same way that no two people get exactly the same cancer even though they might carry the same genetic alterations, we know little about how one individual's disease will interact in the context of their other genes."

One major obstacle to accurately predicting how a disease plays out in individual patients, Katsanis says, is our poor understanding of "second-site" changes in DNA. These so-called modifiers are alterations in other genes that can affect the functions of the genes that contribute directly to a given disease.

"Every disease can be considered complex because of modifiers," says Katsanis. "And we know very little about modifiers, what they are and how they affect disease progression. In the case of ciliary diseases where there is a risk of retinal degeneration and blindness, we want to be able to use a person's genetic information to predict whether or not he or she will go blind and how quickly."

To identify modifiers of ciliary diseases, the team of scientists examined DNA from patients of northern European descent and from their parents and looked for common changes in the RPGRIP1L gene, which already was known to be defective in some but not all ciliary diseases. Although the frequency of any given change in DNA sequence was rare, several changes appeared only in patients with ciliary disease and not in healthy people, while some changes appeared more frequently in patients than in healthy people. One particular change in the RPGRIP1L gene, called A229T, was seen frequently in DNA from patients who had lost some vision but was absent in DNA from patients who had not lost vision.

As individual changes in single genes are difficult to study in people, the team turned to fish to learn how the A229T change in the RPGRIP1L gene affects cells. Like humans, fish also have a gene very similar to RPGRIP1L. In addition, fish are transparent in their early stages of development, which makes it easier to see how individual changes in genes can affect cellular function, structure or development. When the researchers reduced the amount of RPGRIP1L in fish, the animals developed short and stunted body structures and abnormal tails. When normal RPGRIP1L was added back into these same fish, the fish developed more normal body lengths and tails. However, when RPGRIP1L with the A229T change was added back to the fish, they remained short and stunted. So the researchers concluded that the A229T change must prevent RPGRIP1L from working properly.

The team then investigated why the A229T change in RPGRIP1L might lead to retinal degeneration and blindness in people. To do this, they looked for other proteins that interact with the RPGRIP1L protein by fishing the protein out of eye cells and examining what was stuck to it. They found one protein that stuck to RPGRIP1L but did not stick to RPGRIP1L with the A229T change. This protein interaction must be important for retinal function, they concluded, and loss of this interaction may explain how the A229T change in the RPGRIP1L gene increases the risk for retinal degeneration in patients with ciliary diseases caused by other genes.

Ciliary diseases can cause a variety of symptoms in patients, including kidney failure, nervous system defects, extra fingers and toes, and progressive blindness. According to Katsanis, whether a patient goes blind depends on modifiers like A229T. "A229T increases one's risk 10 percent to go blind," says Katsanis. "But it's only one single genetic change of many possible. Now we want to collect all modifier information so we can develop specific drug information and specific treatment regimens."


Contact: Audrey Huang
Johns Hopkins Medical Institutions

Related medicine news :

1. Study reports success in treating a rare retinal disorder
2. Growth factor TGF-B helps maintain health of retinal blood vessels
3. Eye Cells Believed to Be Retinal Stem Cells Are Misidentified
4. Retinal Gene Is Linked to Childhood Blindness
5. Cell death from cytomegalovirus may bring new life to treatment of retinal disease
6. CA$2.4 million toward gene therapy for human degenerative retinal diseases
7. Anti-VEGF drugs for retinal diseases could have serious side effects, scientists caution
8. Anti-VEGF Drugs for Retinal Diseases Could Have Serious Side Effects, Scientists Caution
9. Painkiller May Prevent Diabetes-Related Retinal Damage
10. Severe retinal hemorrhaging is linked to severe motor vehicle crashes
11. MicroRNAs appear essential for retinal health
Post Your Comments:
(Date:6/24/2016)... ... ... Those who have experienced traumatic events may suffer from a complex set ... drug or alcohol abuse, as a coping mechanism. To avoid this pain and suffering, ... traumatic event. , Trauma sufferers tend to feel a range of emotions, from depression, ...
(Date:6/24/2016)... ... ... Marcy was in a crisis. Her son James, eight, was out of control. Prone to ... , “When something upset him, he couldn’t control his emotions,” remembers Marcy. “If there ... my other children and say he was going to kill them. If we were ...
(Date:6/24/2016)... ... 2016 , ... Global law firm Greenberg Traurig, P.A. announced that 20 Florida ... their peers for this recognition are considered among the top 2 percent of lawyers ... as members of this year’s Legal Elite Hall of Fame: Miami Shareholders Mark ...
(Date:6/24/2016)... (PRWEB) , ... June 24, 2016 , ... Comfort Keepers® ... American Cancer Society and the Road To Recovery® program to drive cancer patients to ... and other adults to ensure the highest quality of life and ongoing independence. ...
(Date:6/24/2016)... ... June 24, 2016 , ... People across the U.S. are sharpening ... Talker Award, an essay contest in which patients and their families pay tribute to ... at the 2016 National Society of Genetic Counselors (NSGC) Annual Education Conference (AEC) this ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... -- According to a new market research ... Safety Pen Needles), Needle Length (4mm, 5mm, 6mm, 8mm, ... Purchase (Retail, Non-Retail) - Trends & Global Forecasts to ... for the forecast period of 2016 to 2021. This ... 2021 from USD 1.65 Billion in 2016, growing at ...
(Date:6/23/2016)... 23, 2016  MedSource announced today that it ... software solution of choice.  This latest decision demonstrates ... to their clients by offering a state-of-the-art electronic ... establishes nowEDC as the EDC platform of choice ... clients.  "nowEDC has long been a preferred EDC ...
(Date:6/23/2016)... , June 23, 2016  In a startling report released today, ... their residents by lacking a comprehensive, proven plan to eliminate prescription ... definitive ranking of how states are tackling the worst drug crisis ... four states – Kentucky , New ... Vermont . Of the 28 failing states, three – ...
Breaking Medicine Technology: