Ciliary Disease Genetic Modifier Identified

Two people have the same genetic disease. One of them goes blind in childhood, the other much later in life. It is a phenomenon that has intrigued researchers for years, and is a focus of the field of epigenetics, the study of changes in gene expression caused by mechanisms other than changes in the underlying DNA sequence.

One example currently under study is a group of genetic diseases called ciliopathies, or ciliary diseases, which include Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Joubert syndrome. Findings published online in May 2009 at Nature Genetics report on a single gene already linked to two of these diseases which seems to increase the risk of progressive blindness in other ciliary diseases(1).

Ciliary diseases are genetic disorders of the cellular cilia or the cilia anchoring structures, basal bodies, typified by malfunctioning cilia. They can cause a range of symptoms in patients, including nervous system defects, extra fingers and toes, kidney failure, and progressive blindness.(2,3)

“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.” says Nicolas Katsanis, Ph.D., associate professor of ophthalmology and molecular biology and genetics at the Johns Hopkins School of Medicine.

Limited Predictability

Current ability to predict how much a genetic disease may affect an individual is limited, even when changes in particular genes have been recognized and identified with specific diseases.

One obstacle to accurately predicting what course a disease takes in individual patients, according to Katsanis, 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.”

Finding Genetic Disease Modifiers

To establish modifiers of ciliary diseases, the team of scientists studied DNA from patients of northern European descent and from their parents. They looked for common changes in the RPGRIP1L gene (retinitis pigmentosa GTPase regulator-interacting protein-1 like), which was previously known to be defective in some but not all ciliary diseases.

Even though single changes in DNA sequence proved to be rare, a number of changes appeared only in patients with ciliary disease and not in healthy people. Furthermore, 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 it is impractical to study individual changes in single human genes, the team used fish to learn how the A229T change in the RPGRIP1L gene affects cells. Fish also have a gene very similar to RPGRIP1L. Fish are also transparent in early stages of their development; this makes it easier to see how individual changes in genes can affect cellular function, structure or development.

Researchers first reduced the amount of RPGRIP1L in the fish. The result was the animals developed short, 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. But when RPGRIP1L with the A229T change was added back to the fish, they remained short and stunted. Researchers concluded that the A229T change prevents RPGRIP1L from expressing properly.

Retinal Degeneration and Blindness

The research team then studied possible reasons why the A229T change in RPGRIP1L might lead to retinal degeneration and blindness in humans. To do this, they looked for other proteins that interact with the RPGRIP1L protein by extracting the protein out of eye cells and examining what was attached to it.

They identified one protein which stuck to RPGRIP1L but did not stick to RPGRIP1L with the A229T change. This protein interaction must be important for retinal function, they reasoned, 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.

“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.”


1. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies
Hemant Khanna, et al.
Nature Genetics Published online: 10 May 2009 | doi:10.1038/ng.366

2. Beales P, Elcioglu N, Woolf A, Parker D, Flinter F (1999). “New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey”. J. Med. Genet. 36 (6): 437–46. PMID 10874630.

3. Saraiva, JM, Baraitser M (1992) Joubert syndrome: a review. Am. J. Med. Genet. 43: 726-731

Image: Gerd Alberti and Uwe Kils CC BY-SA 3.0,