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Updated: Jul 1, 2026
Mouse Eye Enucleation for Remote High-throughput Phenotyping
Published on: November 19, 2011
Identification of candidate genes for human retinal degeneration loci using differentially expressed genes from mouse
Christina Demos1, Mausumi Bandyopadhyay, Bärbel Rohrer
1Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA.
Purpose:
Retinal degeneration (RD) is a complex mechanism that appears to involve many biologic processes including oxidative stress, apoptosis, and cellular remodeling. Currently there are 51 mapped, but not identified, RD human disease loci.
Methods:
To assign possible disease genes to RD loci, we have used a comparative genomics procedure that incorporates microarray gene expression data of three independent mouse models for photoreceptor dystrophy (rd1, rd2, and constant light-damage in BALB/c mice), human ortholog data, and databases of known chromosomal locations involved in human RD. Immunohistochemistry and enzyme activity assays were used to further characterize a candidate gene product.
Results:
Our analysis yielded candidate genes for four mapped, but unsolved, human chromosomal locations and confirmed two previously identified monogenic disease loci for human RD, thus validating our approach. PLA2G7 (phospholipase A2, group VII; PAF-AH, Lp-PLA2), a candidate for a dominant form macular dystrophy (Benign Concentric Annular Macular Dystrophy [BCMAD]), was selected for further study. The PLA2G7 enzyme is known to mediate breakdown of oxidatively damaged phospholipids, a contributor to oxidative stress in the retina. PLA2G7 protein was enriched in mouse photoreceptor inner and outer segments. In the rd1, rd2, and BALB/c mice exposed to constant light, retinal tissue activity levels, but not plasma levels, were significantly reduced at the onset of photoreceptor cell death.
Conclusions:
We have shown that this comparative genomics approach verified existing RD genes as well as identified novel RD candidate genes. The results on the characterization of the PLA2G7 protein, one of the novel RD genes, suggests that retinal tissue PLA2G7 levels may constitute an important risk factor for BCMAD. In summary, this reverse mapping approach, using accepted mouse models of human disease and known human RD loci, may prove useful in identifying possible novel disease candidates for RD and may be applicable to other human diseases.
Insights
This study used comparative genomics to identify novel genes for retinal degeneration (RD). Researchers found PLA2G7 may be a risk factor for Benign Concentric Annular Macular Dystrophy (BCMAD).
Area of Science:
- Genomics
- Ophthalmology
- Molecular Biology
Background:
- Retinal degeneration (RD) involves complex biological processes like oxidative stress and apoptosis.
- Numerous human disease loci for RD are mapped but not yet identified.
Purpose of the Study:
- To identify novel genes associated with retinal degeneration loci using a comparative genomics approach.
- To validate the approach by confirming known RD genes and identifying new candidates.
Main Methods:
- Comparative genomics integrating mouse models (rd1, rd2, BALB/c light-damage) with human RD loci data.
- Microarray gene expression analysis, human ortholog data, and database mining.
- Immunohistochemistry and enzyme activity assays for candidate gene characterization.
Main Results:
- Identified candidate genes for four unsolved human RD loci and confirmed two known loci.
- Selected PLA2G7 (phospholipase A2, group VII) as a candidate for Benign Concentric Annular Macular Dystrophy (BCMAD).
- Found reduced retinal PLA2G7 activity in mouse models at the onset of photoreceptor cell death.
Conclusions:
- The comparative genomics approach successfully verified known RD genes and identified novel candidates.
- Retinal PLA2G7 levels may be a significant risk factor for BCMAD.
- This reverse mapping strategy is valuable for discovering novel RD genes and applicable to other diseases.
