Genes
Chat Highlights
August 17, 2005

On Wednesday, August 17, 2005, Dr. Jeff Henderer, a glaucoma specialist at Wills, and the glaucoma chat group discussed "Genes."

Moderator:  Dr. Henderer, have researchers made much progress in glaucoma genetics?

Dr. Jeff Henderer:  It turns out that some glaucoma is inherited.  So far, nine DNA regions that harbor genes associated with open-angle glaucoma, the most common form, have been identified.  The disease-causing genes -- myocilin, optineurin, and WDR36 -- have been discovered for three of those nine regions.

P:  Are such studies difficult to do?

Dr. Jeff Henderer:  Yes. For instance, the WDR36 study involves a large number of patients in a family, testing blood to see if those affected have a particular gene, then comparing that gene to a normal sample to see if it is a true mutation.

P:  Will you please explain what a gene is?

Dr. Jeff Henderer:  A gene is an area of DNA on a chromosome containing information that will eventually be turned into a protein, which will perform some function in a cell.

P:  What chromosomes are these genes on?

Dr. Jeff Henderer:  The most recent one is on chromosome 5. The myocilin mutation is on chromosome 1, infantile is on chromosome 2, pigmentary is on chromosome 7.

P:  How will information about genes be useful?

Dr. Jeff Henderer:  I think there are two ways that information about genes can be useful.  First, you (or your children) can be tested to see if the gene is present.  That can help identify people at risk.  Second, it appears that some genetic makeups are more likely to respond to certain types of medication.  That will allow more effective therapy.

Moderator:  Is the difference between these genes and their function relative to glaucoma known?

Dr. Jeff Henderer:  There is no clear understanding about how the mutation leads to disease.  For instance, the protein product of one glaucoma gene identified so far is the protein myocilin. No one knows how this defect causes glaucoma, and since only about 4% of adults with open-angle glaucoma have this mutation, it's not clear that it is the mechanism.  There are certainly more causes that we don't yet know.

P:  A few years ago we had a chat with Dr. George Spaeth cut short by a storm or computer troubles.  It wasn't clear to me at that time whether the gene(s) act by predisposing to high IOP (intraocular pressure) or other risk factors, or by directly predisposing the optic nerve to damage.  Is it one or both of these?  Presumably with the secondary glaucomas, like pigmentary, it's the former.

Dr. Jeff Henderer:  Well, I can't add too much to your excellent comment.  I agree with you that there are some diseases that seem to act through high IOP (pigmentary comes to mind) and some that act perhaps because the optic nerve is "wimpy," as in normal-tension glaucoma.  My guess is that a variety of factors can lead to the optic nerve disease we call glaucoma.  What is certain is that all glaucoma seems to kill cells by the common pathway of apoptosis, or cell suicide.

P:  What is an optineuron?

Dr. Jeff Henderer:  Optineuron was the most recently described defect -- recently, that is, before the WDR36 gene.

[Editor's Note: "Mansoor Sarfarazi, Ph.D., professor of human genetics and director of the Molecular Ophthalmic Genetics Laboratory, Surgical Research Center, University of Connecticut Health Center, and colleagues first reported in Science (Feb. 8, 2002) about adult-onset primary open-angle glaucoma caused by mutation in GLC1-E, now commonly referred to as optineurin (OPTN).]

P:  Have any genes been found that relate to congenital glaucoma in children?

Dr. Jeff Henderer:  In 1997, Dr. Sarfarazi and colleagues provided evidence that mutations in the gene CYP1B1 are responsible for congenital glaucoma in children.  I should also mention that Dr. George Spaeth, working with Dr. Sarfarazi and others from the Glaucoma Foundation in New York, including Drs. Robert Ritch and Jeffrey Liebmann, also identified a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1.

P:  How does the gene testing work?  A simple blood test?  Does insurance cover it?  What can it predict?

Dr. Jeff Henderer:  Gene testing is a blood test or, more recently, a cheek swab.  I am not sure that it is covered by insurance.  It would be able to predict glaucoma if you carried the gene that all your family who got glaucoma also had.  Otherwise, I'm not sure we know enough about the long-term history of these mutations.

P:  The new glaucoma gene they found in me is a novel frame shift mutation on chromosome 2, 1062dup16_1090del6.  It involves duplication 16 bases after nucleotide 1062 and deletion of 6 bases after nucleotide 1090.  Do you think I could name my mutation?  It was found to have caused my daughter's PCG (primary congenital glaucoma).  My daughter has the other recessive gene from her Dad, a common one called CYPB1B1.

Dr. Jeff Henderer:  I am impressed by the extent to which this has been worked out for you.  I don't know how names are granted.  It would be best to talk with the researchers who helped identify it.

P:  Thanks to Quest labs, who did the study at no charge.

Dr. Jeff Henderer:  Great for Quest labs!

P:  I will be the first woman in the world to have my twin pregnancy tested for the glaucoma mutation (in each) for prenatal diagnosis.  I will know in two weeks whether or not they have the two mutations (recessive).

Dr. Jeff Henderer:  I've never heard of that and am impressed.

P:  It was a 1 in 10,000 birth event that my little girl would have glaucoma.

Dr. Jeff Henderer:  Good point.  The incidence of congenital glaucoma is about 1 in 22,000.

P:  Have any genes for closed-angle glaucoma been found?

Dr. Jeff Henderer:  Closed-angle glaucoma remains a big problem.  It is not common in America, so it's tough to find the families for it.  But it is a huge problem in other parts of the world, so I have to assume that it is being worked on.

P:  Should the children of parents with open-angle glaucoma have a gene test, assuming there is one?

Dr. Jeff Henderer:  Well, right now there have been tens of specific mutations identified.  Some don't seem to cause glaucoma, as others do.  I suppose it is reasonable to have your blood drawn, so that once we get a better understanding of where to look, the opportunity exists to test you, even years in the future.  There was a gene test that was promoted a few years ago.  I'm not sure it's still available, and I'm not sure anyone ever ordered it.

P:  I have the nail patella syndrome (NPS) on chromosome 9.  We NPS patients lack the protein lmx1b, which affects the glomular basement membrane of the kidneys, and also can affect the trabecular meshwork.  So glaucoma is part of NPS in our family.

Dr. Jeff Henderer:  I am glad you mentioned NPS.  There are a few other rare conditions (yours would qualify as rare in my book) where the gene has been identified.  Axenfeld-Reiger would be another.

P:  I am 57-years old, my son is 21-years old, and we both have glaucoma.  Thirty years ago, my father, who died in his early 60's, was diagnosed with glaucoma.  Would you advise my son and me to have gene testing for the future generations?

Dr. Jeff Henderer:  Well, that would be useful if you knew what mutation you carried.  If you two could be screened against the known mutations and had one, then it makes sense to me to test future generations for that condition.

That brings up the issue of genetic pre-marital testing.  That testing is done commonly in some communities because of other eye diseases.  In glaucoma, it seems that we don't have enough information yet for the most common forms of the disease.

P:  So people would be advised not to have children if there's a strong likelihood their offspring might have glaucoma?  That seems drastic to me.

Dr. Jeff Henderer:  I agree with you.  I have a patient whose mother is upset that she's the source of the mutation, and I keep telling her that her daughter is a beautiful young woman who happens to have one bum eye.  There are worse things than that.  Just remember that we all carry a half dozen or so lethal mutations that, if expressed, would have been the end of us.  Yet the human species survives!

P:  Until there's available gene therapy, does any of this have any clinical relevance to those of us who have glaucoma?  For example, I have pigmentary glaucoma.  Outside of a research setting, I wonder if any of my doctors would be supportive of my being tested for a defective gene, since it would seem to be of purely academic interest (for me, maybe not my daughter).

I know that the pigment is rubbing off of my posterior iris, but would it affect the course of my treatment to know whether there's an underlying genetic defect in the iris pigment epithelium, or whether there's merely an anatomical reason for the rubbing of iris against lens/zonules?  Seems I'll still be instilling Xalatan to control IOP.  A genetic defect would be an academic concern.

Dr. Jeff Henderer:  I'm in complete agreement with you.  It seems to me that in your condition in particular (and in your daughter's case) you are born the way you are born.  You can change the pigment shedding by laser iridotomy and, if done early in life, I guess you could eliminate any pigment shedding and stop the disease, as this is an anatomical disease.  It's not so easy to get the average patient a new trabecular meshwork.

Moderator:  Thank you so much, Dr. Henderer, for your time and for sharing your knowledge with us.

Dr. Jeff Henderer:  This has been a good conversation.  I hope it has been helpful.

Note: At a later date, Dr. Henderer kindly expanded on his comments in the chat room, as follows:

I suppose the future of most neurodegenerative diseases lies in either gene therapy (that would be both gene replacement and gene activation) or in genetic “profiling” (means tailoring medical therapy to genetic profiles or using genetic profiles to more accurately predict the likelihood of disease and disease severity).  Or, perhaps, a combination of the two.

Important first steps have been taken in some of these areas. I recall an ARVO poster about a viral vector that could infect trabecular meshwork cells, offering hope that replacement copies of a defective gene could be delivered to diseased eyes.  

To my knowledge, the recent mouse work with optic nerve regeneration using a knock-out model (the investigators genetically altered the mouse to turn off a suppressor nerve growth gene) was the first time anyone has demonstrated optic nerve regeneration.  It is, of course, not possible at this time to deactivate any of our genes, but this experiment at least proved that central nervous system regeneration is possible in vertebrates.

That information, combined with Christopher Reeve’s spinal cord work, offers the first tangible hope that we may one day be able to reverse blindness from glaucoma –- not just prevent blindness.  A growing body of work is looking at genetic profiles to see who may respond to meds and who seems to get worse despite treatment.

Recent work from France looked at one genetic profile and found that meds didn’t work well for this genotype, and surgery would be a better option.  Dr. Doug Rhee, and probably others too, have been working on tissue culture models to see if certain drugs work.  Dr. George Spaeth published a very important (but, I’m afraid, perhaps largely missed or ignored) paper documenting how a group of patients in his practice with a certain genetic mutation progressed at a much higher rate than those that did not have this mutation.

These efforts represent the first work in gene “therapy” for glaucoma.  And I haven’t even mentioned all the work being done in Israel to create a vaccine for glaucoma (the assumption being that glaucoma is an autoimmune disease).  For the moment, none of these issues really helps anyone.  We can only test commercially for one mutation associated with glaucoma.  That test was available, but I’m not aware of anyone ordering the test, so I’m not sure it’s still available.

We have only begun to scratch the surface when it comes to cataloging the genetic defects associated with glaucoma.  We have no idea how environment might interact with genetics to create disease. In other words, our knowledge is so incomplete that we don’t know what to test for.  Even the most common mutation is only present in 4% of adult primary open-angle glaucoma.  Further, we have no idea what role this mutated protein plays normally and why an abnormal copy would be associated with, or lead to, disease.  We have no idea how to predict if the mutation will lead to disease.  All we have done is identified mutations in certain families with glaucoma.  But it’s a start!

My hunch is that one day we will no longer have a disease, “open-angle glaucoma.”  Rather we will have a family of genetic mutations that carry a known risk of developing primary optic nerve rot (Doug Anderson’s term for glaucoma) and have defined treatment algorithms –- much like certain subtypes of breast cancer respond to one chemo agent and not another.  We will be able to block nerve growth suppressor proteins and thereby regenerate optic nerve tissue, and we will be able to block apoptosis in existing nerve cells.  Lowering IOP will only be part of the treatment.

I believe this will help patients, but I’m not sure how it will help a world increasing stratified into “haves” and “have nots” with limited resources.  In parallel to medical advances, there will need to be clear privacy laws that protect individuals with genetic “defects” from being discriminated against.

For example, no one will agree to be genetically profiled if it means that you will lose your health insurance because you have been born with a pre-existing condition that means you might one day get sick.  The world’s first amniocentesis to assess a mutated gene associated with congenital glaucoma is about to be done. I’d want to know too, but will those children be uninsurable? With health care expenses set to explode with the baby boomers due to volume of people and increased life expectancy, you can imagine the pressure from employers, insurers, and the government to control costs.  You can easily image even worse scenarios, as genetics could easily be warped in a way to highlight differences among human beings instead of how we are all the same.

On August 24, Dr. Wilson discussed "Secondary Glaucoma" in the Chat room. Click here for highlights of that meeting.

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