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R. W. Nickells, J. A. Dietz, Y. Li, L. M. Chung, C. L. Schlamp, B. S. Yandell; Rgcs1, a Dominant QTL That Affects Retinal Ganglion Cell Death After Optic Nerve Crush. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4063.
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© ARVO (1962-2015); The Authors (2016-present)
. Glaucoma is a complex genetic disease. Although important advances have been made in identifying genes associated with inherited forms of glaucoma, little is known about the genes that affect susceptibility to this disease. One of the facets of glaucoma that could be influenced by susceptibility alleles is ganglion cell death. We have used an experimental genetics approach with inbred mice to help identify candidate genes for this process.
. Previously we showed that ganglion cells in DBA/2J mice were resistant to an optic nerve crush, while BALB/cByJ mice exhibit susceptibility. Crosses of these mice showed that this trait could be inherited in a dominant fashion involving relatively few loci. A mapping population of 200 F2 animals was bred, subjected to crush, and phenotyped for cell loss. The most resistant mice (≥64% cells remaining) and most susceptible mice (≤54%) were used for a genome wide screen using 65 microsatellite markers. Linkage analysis was performed using Rqtl software. Computer (in silico) analysis of this region was performed using the MGI data base at JAX. Genes in this region were cross-referenced to expression profiles published in various microarray studies.
. Linkage analysis identified a single significant QTL on chromosome 5 spanning 25 cM (Chr5.34 to Chr5.59, LOD = 5.17). This locus was designated Rgcs1, for Retinal ganglion cell susceptible 1. Mice carrying 1 or 2 DBA/2J alleles exhibited significantly less cell loss than mice homozygous for the BALB/c allele (P=4.4e-7). In silico analysis of this region revealed 578 genes or ests, of which 25 carried 35 single nucleotide polymorphisms that created nonconserved amino acid changes. Four genes in this region are also highly expressed or enriched in the ganglion cell layer of the mammalian retina. Two genes have previously been identified as susceptibility alleles in other neurodegenerative diseases. Using overlapping criteria, we identified 7 possible candidate genes that could affect the process of ganglion cell death. RT-PCR analysis confirmed that all 7 genes are expressed in the mouse retina.
. A single region of the mouse chromosome 5 confers resistance to a lesion of the optic nerve in a dominant fashion. Since a similar molecular cell death program is activated by crush and glaucoma, this region may contain a susceptibility allele that affects resistance to glaucoma in the human population.
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