12# 凤凰涅盘
11) IMPDH1 mutations - Depending on the area of the gene affected, IMPDH1 mutations can cause either LCA or a form of autosomal dominant RP classified as RP10. This spectrum of mutations and disease phenotypes has been well characterized by investigators such as Dr. Steve Daiger at the University of Texas in Houston. TX. Dr. Peter Humphries and his coworkers in Dublin, Ireland have applied gene therapy to a mouse model of RP10 and found it to prevent photoreceptor degeneration and to preserve synapse conductivity. It has yet to be demonstrated though that this work is applicable to the LCA disease phenotype.
12) RDH12 mutations – There are many members of the retinol dehydrogenase (RDH) family of protein enzymes, classically thought to participate in vitamin A molecular conversion in the retina. Recent work though indicates that the specific RDH12 member of this family protects the retina from oxidative damage with disruption of the gene and protein leading to retinal degeneration. A “knockout” mouse has been engineered in which the RDH12 gene is disrupted so the biological effects of deleting the gene and protein can be studied. With this model available, gene replacement therapy can also be performed to test for safety and efficacy of the procedure before attempting human clinical trials.
Laboratory Experimentation:
13) RD3 mutations LCA12 - Although the RD3 mouse model of retinal degeneration has been known for many years (1993), it was only in 2007 when the gene mutation causing the disease process was identified by a large consortium of investigators. The RD3 protein seems to perform many important functions in the retina Molday and coworkers have recently shown that it is critical for synthesis of a signaling molecule in the photoreceptor cells called cyclic GMP, lack of which could lead to photoreceptor cell death. In the mouse, a variable phenotype is observed with siblings with the exact same mutation exhibiting different levels of degenerative severity. Danciger and colleagues have begun to catalog genetic modifiers for this effect, i.e., genes/alleles that influence the inherited degenerative process. Although preclinical therapeutic experiments are yet to start on the RD3 mutation, excellent rodent and canine models are available that are similar to humans with the RD3 mutation.
14) SPATA7 – Mutations in the human SPATA7 gene causing LCA were only reported in the scientific literature in 2009. Since then, a few publications have described the screening of SPATA7-specific patients within the LCA population ( 1.7% of cases of childhood retinal dystrophy), the genetic spectrum of SPATA7 mutations and the delineation of the associated disease phenotype. Even though there is severe visual loss in infancy, some preservation of photoreceptor structure has been described in the central retina. This gives hope for successful therapy in restoring at least some visual function in an appropriate animal model and ultimately in the human.
15) TULP1 mutations – Some mutations in the TULP1 gene can lead to LCA while others lead to retinal degeneration that is of an RP phenotype. A number of clinical reports are in the scientific literature describing the characteristics of the degeneration in specific families (Suranamese, Algerian and Dominican). A good mouse mode has been developed and characterized. It demonstrated an early-onset retinal degeneration but seems to be normal in other regards. The availability of the model would allow for testing of different types of therapy in the future.
©2012 The Foundation for Retinal Research and its licensors.
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