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These families aren't Dr. Walter's long-lost cousins, however. They are the more than 1000 individuals whose stories make up one of the world's best collections of information on rare genetic eye diseases.
Dr. Walter is a human geneticist whose focus in ophthalmology evolved from his post-doctoral work in male sexual development. The research team he was with at Cambridge successfully cloned the gene that switched on testes development in embryos. Without this gene, called SRY, embryos become females. He left Cambridge with a fascination for how the body makes decisions that lead to the development of an egg to an adult organism.
The best way scientists have of studying the genes that control overall development is to focus on a simpler model of development in Dr. Walter's case, the genes involved in organ formation; in particular, the testes or the eye. These are good research models to study throughout the life of an organism because their absence does not cause embryonic death, as is the case with kidneys or liver. Since much of the eye comes from the same tissue that makes up the brain, genes involved in eye development may have parallels in the brain.
Dr. Walter describes the database of information from more than 1000 people compiled over decades by the Head of the U of A's Department of Ophthalmology, Dr. Bill Pearce, and more recently by colleague Dr. Ian MacDonald, as "the bread and butter of my human genetics research." The size and quality of the database offers a rich resource for a number of research topics. When Dr. Walter found that defects of the front part of the eye the anterior (front) segment were distinctive features of the database information, he initiated several projects that may someday yield valuable tools to fight a major cause of blindness: glaucoma.
The anterior segment of the eye includes the visible structures of the cornea and the iris. The iris (the coloured part of the eye) meets the cornea (the transparent bubble covering the eye) at a juncture point. The juncture forms an angle, called the angle of the anterior segment, and is the primary drainage route of the aqueous humour, the clear liquid inflating the eye.
The constant circulation of aqueous humour through the eye and into the lymphatic system regulates eye pressure. If the angle of the anterior segment is not formed correctly, aqueous humour cannot drain efficiently, resulting in over-inflation of the eye. The pressure this causes at the back of the eye can eventually kill the optic nerve, leading to blindness. Glaucoma which occurs with approximately the same frequency as heart disease, is estimated by the World Health Organization to become the leading cause of blindness within ten years.
Some, but not all, genes responsible for glaucoma have been discovered. Researchers in the U.S. found a gene late last year known as TIGR that is responsible for primary open-angled glaucoma, where the angle of the anterior segment looks fine but affected people still get glaucoma. Surprisingly, what the American research group also discovered was that, although TIGR is rare, 4% of all general glaucoma patients had some mutation of this gene. Since people respond differently to glaucoma drugs, it could be that varying responses are due to the involvement of different genes that, once identified, could lead to refined treatments in the future.
Dr. Walter heads an international collaboration to identify the major genetic causes of glaucoma. Using DNA samples and molecular applications on tissue collected from a family from Alberta and the Maritimes and two families in Great Britain, he hopes to find what causes two rare eye malformations called iridogoniodysgenesis anomoly (IGDA) and Axenfeld-Rieger anomaly (ARA). More than one-half of patients with these conditions develop glaucoma.
Both IGDA and ARA have related "cousin" diseases, Iridogoniodysgenesis Syndrome (IGDS) and Axenfeld-Rieger Syndrome (ARS), both of which share the same eye malformations as IGDA and ARA, yet also result in other physical characteristics, including abnormal formations of the jaw and teeth. Recently a gene was identified on chromosome 4 for ARS. Dr. Walter also found a mutation in chromosome 4 in the IDGS family he is working with, demonstrating a shared genetic cause for the IGDS and ARS. Because ARA has been mapped to chromosome 6 and shares the same angle malformations as IGDA, Dr. Walter suspects that a common gene there might be mutated in both diseases.
Ironically, many people with IGDS and with IGDA can be diagnosed at a glance. Their pupils are surrounded by a prominent white ring caused by the anterior segment angle defect. The white is the iris sphincter muscle, now visible in the absence of the top layer or two of coloured iris. However, for the 10% of people in IGDS families who do not have the visible white ring, genetic testing will now reveal the mutation.
As with Huntington's Disease (a fatal condition determined by the presence of a single mutated gene), the children of IGDA and IGDS patients have a 50% chance of inheriting the mutated gene. The gene is dominant, meaning that if they have inherited the gene, they will develop the condition. However, the gene is variably expressed, which is why some IGDA and IGDS patients do not have the tell-tale white band around the pupil, just as with Huntington's disease the variable expression results in different ages of disease onset.
Variable expression in IGDA leads Dr. Walter to believe that many people in the general population may also be carrying the mutated gene for this specific condition. Identification of the precise genetic causes of IGDA and ARA could lead to early detection of glaucoma and treatments targeted at specific genes.
Dr. Michael Walter is an AHFMR Scholar in the University of Alberta's Department of Ophthalmology and Medical Genetics. He also receives funding from the Medical Research Council of Canada.
Testing for Glaucoma |
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Known as the silent disease, glaucoma is often only detected when peripheral vision loss occurs. By that time, damage to the optic nerve is irreversible. If glaucoma can be detected before symptoms appear, treatments can delay damage significantly and save vision. A simple test performed by an ophthalmologist can determine increased eye pressure, the first sign of the disease, but this is not standard practice. Many people are only given the test when the signs of vision deterioration appear, which is often too late. Since the incidence of glaucoma is rising, scientists at the U of A's Ocular Genetics Department are working with ophthalmologists to encourage |
more frequent testing and enable early detection and treatment. As Dr. Walter says, "People should have glaucoma tests a lot more than they do."For more information on glaucoma please call the Canadian National Institute for the Blind in Edmonton at (403) 488-4871 and in Calagary (toll-free) at 1-800-376-2642. |
For more information on glaucoma, please check the following website:
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