Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice.
BACKGROUND
Intrinsic apoptosis of neuronal somas is one aspect of neurodegenerative diseases that can be influenced by genetic background. Genes that affect this process may act as susceptibility alleles that contribute to the complex genetic nature of these diseases. Retinal ganglion cell death is a defining feature of the chronic and genetically complex neurodegenerative disease glaucoma. Previous studies using an optic nerve crush procedure in inbred mice, showed that ganglion cell resistance to crush was affected by the Mendelian-dominant inheritance of 1-2 predicted loci. To assess this further, we bred and phenotyped a large population of F2 mice derived from a resistant inbred strain (DBA/2J) and a susceptible strain (BALB/cByJ).


RESULTS
Genome wide mapping of the F2 mice using microsatellite markers, detected a single highly significant quantitative trait locus in a 25 cM (58 Mb) interval on chromosome 5 (Chr5.loc34-59 cM). No interacting loci were detected at the resolution of this screen. We have designated this locus as Retinal ganglion cell susceptible 1, Rgcs1. In silico analysis of this region revealed the presence of 578 genes or expressed sequence tags, 4 of which are highly expressed in the ganglion cell layer of the mammalian retina, and 2 of which are suspected susceptibility alleles in chronic neurodegenerative diseases. In addition, 25 genes contain 36 known single nucleotide polymorphisms that create nonsynonymous amino acid changes between the two parental strains. Collectively, this analysis has identified 7 potential candidate genes that may affect ganglion cell death.


CONCLUSIONS
The process of ganglion cell death is likely one of the many facets of glaucoma susceptibility. A novel dominant locus has been identified that affects sensitivity of ganglion cells to optic nerve crush. The allele responsible for this sensitivity may also be a susceptibility allele for glaucoma.
Dietz
Joel A
JA
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA. jadietz@wisc.edu
Li
Yan
Y
Chung
Lisa M
LM
Yandell
Brian S
BS
Schlamp
Cassandra L
CL
Nickells
Robert W
RW
D033942:Adaptor Proteins, Vesicular Transport; D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005901:Glaucoma / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009409:Nerve Crush; D009419:Nerve Tissue Proteins / Q000235:genetics; D020221:Optic Nerve Injuries / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012162:Retinal Degeneration / Q000235:genetics; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology
D033942:Adaptor Proteins, Vesicular Transport; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C503127:Sparcl1 protein, mouse; C095992:complexin I