Molecular Genetics of Juvenile Onset Glaucoma

Glaucoma is a major human eye disease which has blinded about 80,000 out of the 2,000,000 Americans affected by it. Even though some forms of treatment have been developed, including both medications and surgery, a precise understanding of this disease on the cellular and biochemical level is lacking. Recent medical research advances are allowing scientists to use molecular biology and a technique called reverse genetics to gain understanding of some human disease processes. The reverse genetics approach involves finding out where a gene is located on one of the human chromosomes and using that information to lead to the cloning of the gene responsible for the disorder. The critical element for this research approach is a very large family in which glaucoma is inherited and present in several living generations of the family at once. Such families are rare and the family which we have identified for this study is a very valuable one. The purpose of this project is to initiate a molecular genetic study of a form of juvenile glaucoma which is inherited in a large multigenerational family which we have identified in Michigan. This family is very valuable to our study for several reasons, including the size of the family and the early age of onset. The immediate goals of this project are to collect and begin analyzing diagnostic information and genetic materials from all of the members of this valuable family. Their form of glaucoma, which includes elevated pressure inside the eye, nerve damage, and eventual vision loss, begins young ~ and most of the standard drug therapies do not work well enough to reduce the pressure inside of the eye. In most cases the glaucoma patients have had surgery several times by their late teens, and in one case glaucoma was diagnosed as young as 3 years of age. This grant will allow us to carry out the beginning steps in a reverse genetics approach to this family: collecting information and blood samples and beginning the analysis of where the gene is located on one of the human chromosomes. Finding the location of the gene will take longer than the one year of this project, but it is the first step towards obtaining a cloned glaucoma gene. The long range goal of our research group is to find the gene responsible for causing a type of glaucoma which is very hard to treat with some of the usual kinds of drugs. A cloned glaucoma gene would aid in studies of the underlying biochemical causes of glaucoma and lead to improved methods for treating, and perhaps eventually curing, one form of glaucoma. Such a clone would allow us to study the function of the gene, to develop new assays for potentially therapeutic drugs, and to give much more precise information to patients about what is causing their disease. Such a clone would help us develop tests to distinguish between different kinds of glaucoma so that the optimal therapy might be assigned based on precise understanding of the defect. The advances that will come from cloning a glaucoma gene are sorely needed. In spite of a variety of drug therapies and surgical approaches to glaucoma blindness cannot always be prevented. Many who are not completely blind have reduced vision, and everyone who suffers from glaucoma faces a lifetime of pressure monitoring, visual testing, drug therapies, possibly multiple surgeries, and fear of eventual blindness. The juvenile-onset form of glaucoma which we propose to study is especially frightening because it begins so early in life and there is so little prospect of success with drug therapies. The approach we will use, called reverse genetics, has been used recently with dramatic success to clone genes responsible for diseases such as Cystic Fibrosis. By this approach, researchers use the genetic location of a gene as the mechanism for locating and then cloning a gene which cannot be cloned by the standard methods which require that we know something about the biochemistry, structure and function of the gene product. In the case of Cystic Fibrosis, they first mapped the gene, then used that information to carry out some very sophisticated molecular cloning techniques. The clone they obtained has lead researchers to functional insights about the gene, has allowed them to do genetic screening, and has even lead to an experiment in which a “good” copy of the Cystic Fibrosis gene was used to restore proper functioning to cells with the Cystic Fibrosis defect which were being grown in culture. Many of us are watching with great excitement to see what possibilities for gene therapy will come out of the current studies on the Cystic Fibrosis gene. Similar thinking about glaucoma must await both advances in gene therapy technology and the cloning of a glaucoma gene. With the money from this grant we will preserve genetic materials from this family so that we can eventually find out what chromosome the gene is on and where on that chromosome it is located. We will hire technical assistance and buy supplies needed to obtain blood from members of the family and to produce DNA and cell lines which will give us continued access to genetic material from every member of the family even if they are no longer available for the study. We will begin analyzing genetic markers present in the DNA of each participant, a process which will extend far beyond the 1 year scope of this grant. Once the gene has been mapped we will then have the information we need to proceed towards the cloning of this glaucoma gene.