Ryan and I are headed to Texas next week so I can take part in the following study (this can get pretty technical and is not my usual blog fare, but for those who may be interested, here it is.) I am excited about going and being part of this and a little apprehensive about leaving my kiddos. Please pray for all of us and our children's designated caregivers: Aleesha, Tiffanie, Kristin and Scott, and my parents. Thanks so much for your willingness to help us out. (We leave on Wed. and return on Sat.)
-Linked Retinitis Pigmentosa Carrier Phenotyping Project: The Search for Modifying Factors for Disease Severity
The purpose of this project is to detect genetic factors that influence the clinical consequences of mutations in genes causing X-linked retinitis pigmentosa (RP). Mutations in X-linked RP genes can lead to strikingly different clinical outcomes, even among individuals with the same mutation in the same family. While clinical variation is often seen among males, the most striking differences are seen among females. Phenotypes in “carrier” females can range from no detectible symptoms, to early onset, rapid progression of disease. Finding the factors that account for these differences will improve our understanding of the disease process. Of more importance, though, identifying these factors may suggest ways to slow or arrest the loss of vision in affected individuals. That is, if we can understand what makes individuals with X-linked mutations either asymptomatic or mildly affected, we may be able to use this information to treat patients with more severe symptoms.
The major focus of this project is the X-linked RP gene RPGR (retinitis pigmentosa GTPase regulator) and the clinical consequence of interest is the disease severity in female carriers of RPGR mutations. Mutations in RPGR account for 80% of cases of X-linked RP and affect more than 10,000 Americans. Further, studies suggest that approximately 30% of isolated RP is caused by mutations in RPGR, making mutations in RPGR the most common cause of RP. Males with a mutation in an X-linked gene such as RPGR are almost always affected, because males have only one X-chromosome, but female carriers of an X-linked mutation are often unaffected since females have two X-chromosomes and the second chromosome may provide protection from the mutation. However, many females who carry an RPGR mutation have clinical symptoms of RP, ranging from undetectable or very mild in some cases to severe loss of vision in others.
The project has several key aims. The first aim is to identify, enroll and characterize the families and patients with RPGR mutations. This will be done by Drs. David Birch, Dennis Hoffman, and Dianna Wheaton at the Retina Foundation of the Southwest in Dallas. The goal is to enroll as many individuals with mutations in each family as possible, to evaluate each individual with a panel of tests including advanced retinal imaging, to determine the range of clinical expression associated with each RPGR mutation, and to collect blood and DNA samples for genetic testing. Thus, one outcome of the project will be a comprehensive genotype-phenotype characterization of RPGR mutations.
The second aim is to test the hypothesis that genetic modifying factors may play a role in altering disease severity. We plan to approach this in two ways. First, we plan to investigate the role of two genes that interact with RPGR to determine if slight genetic variations within these genes can affect the behavior of RPGR. Secondly, we plan to test a large class of random genetic variants by microarry analysis in a genome-wide association study.
Finally, the third aim is to extend these studies to clinical variation in males with RPGR mutations.
The detection of factors modifying inherited diseases is a relatively new field of investigation. Completion of the project should substantially expand our understanding of the clinical consequences of mutations causing X-linked RP, and may identify new targets for treatment and prevention of retinal disease.
The purpose of this project is to detect genetic factors that influence the clinical consequences of mutations in genes causing X-linked retinitis pigmentosa (RP). Mutations in X-linked RP genes can lead to strikingly different clinical outcomes, even among individuals with the same mutation in the same family. While clinical variation is often seen among males, the most striking differences are seen among females. Phenotypes in “carrier” females can range from no detectible symptoms, to early onset, rapid progression of disease. Finding the factors that account for these differences will improve our understanding of the disease process. Of more importance, though, identifying these factors may suggest ways to slow or arrest the loss of vision in affected individuals. That is, if we can understand what makes individuals with X-linked mutations either asymptomatic or mildly affected, we may be able to use this information to treat patients with more severe symptoms.
The major focus of this project is the X-linked RP gene RPGR (retinitis pigmentosa GTPase regulator) and the clinical consequence of interest is the disease severity in female carriers of RPGR mutations. Mutations in RPGR account for 80% of cases of X-linked RP and affect more than 10,000 Americans. Further, studies suggest that approximately 30% of isolated RP is caused by mutations in RPGR, making mutations in RPGR the most common cause of RP. Males with a mutation in an X-linked gene such as RPGR are almost always affected, because males have only one X-chromosome, but female carriers of an X-linked mutation are often unaffected since females have two X-chromosomes and the second chromosome may provide protection from the mutation. However, many females who carry an RPGR mutation have clinical symptoms of RP, ranging from undetectable or very mild in some cases to severe loss of vision in others.
The project has several key aims. The first aim is to identify, enroll and characterize the families and patients with RPGR mutations. This will be done by Drs. David Birch, Dennis Hoffman, and Dianna Wheaton at the Retina Foundation of the Southwest in Dallas. The goal is to enroll as many individuals with mutations in each family as possible, to evaluate each individual with a panel of tests including advanced retinal imaging, to determine the range of clinical expression associated with each RPGR mutation, and to collect blood and DNA samples for genetic testing. Thus, one outcome of the project will be a comprehensive genotype-phenotype characterization of RPGR mutations.
The second aim is to test the hypothesis that genetic modifying factors may play a role in altering disease severity. We plan to approach this in two ways. First, we plan to investigate the role of two genes that interact with RPGR to determine if slight genetic variations within these genes can affect the behavior of RPGR. Secondly, we plan to test a large class of random genetic variants by microarry analysis in a genome-wide association study.
Finally, the third aim is to extend these studies to clinical variation in males with RPGR mutations.
The detection of factors modifying inherited diseases is a relatively new field of investigation. Completion of the project should substantially expand our understanding of the clinical consequences of mutations causing X-linked RP, and may identify new targets for treatment and prevention of retinal disease.
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