Disease gene set analysis

Example of retinitis pigmentosa

This case demonstrates how GeneAnalytics can be used in drug discovery. We will use a gene set associated with Retinitis pigmentosa to identify target cells, mechanisms of action and potential drugs. The gene set was obtained from MalaCards - the human disease database, and was used as a gene set in GeneAnalytics: we selected the input species (human), copied the list of genes and ran the analysis to view the matching results.

Retinitis Pigmentosa (RP) is an inherited, degenerative eye disease, characterized by the progressive loss of photoreceptor cells that can eventually lead to blindness. Currently, there is no pharmacological cure for Retinitis Pigmentosa, however, in some patients, disease progression can be attenuated by daily Vitamin A intake.

GeneAnalytics results are divided into several sections: Tissues & Cells, Diseases, Pathways, Gene Ontology terms and Compounds. Each section presents entities, scored and ranked by their degree of matching to the gene set provided, as well as hyperlinks to the evidence-based data sources, a list of matched genes per entity and valuable filters.

The first goal of this analysis is to quickly identify cells associated with the disease.

The first section presents normal expression results. The detailed table on the right shows the matched entities, a list of matched genes and tissue annotations. We can clearly see that Mature rod cells in the eye was the entity that most closely matched the analyzed gene set. These cells are photoreceptors, light-sensory neurons that contain the visual pigment rhodopsin. Rod cells are indeed the primary cells affected by Retinitis Pigmentosa and express many genes that match the analyzed gene set.

When clicking on the number of matched genes, a table opens with information about the genes expressed in the rod cells. These genes are interesting for further evaluation of their functionality and as potential drug targets for Retinitis Pigmentosa.

We can now narrow the search, and run a new query with this focused list of 35 genes that are both associated with Retinitis Pigmentosa and match those expressed in rod cells.

After running the new analysis, we would like to take a look at pathway results. This section provides further understanding of the roles of these genes in health and disease. The provided information lists pathways matching the gene set, including diseases associated with visual transductionthe phototransduction cascade and the visual cycle in the rods. The list of genes involved in each pathway is available by clicking on the number of matched genes.

Each pathway is also linked to its relevant card in PathCards, a novel integrated pathways database, which unifies pathways from multiple data sources based on their overlapping related genes.

The Gene Ontology section presents biological processes and molecular functions associated with this gene set.

In the biological processes section, we note a high matching of the gene set to visual perception, phototransduction, rhodopsin-related signaling and more. You can learn about the genes involved in each process by clicking on the number of matched genes.

The molecular function section results highlights the molecular functions impaired in the damaged Retinitis Pigmentosa rod cells , such as: Phosphodiesterase activity and cGMP binding.

These results stand in line with reports of mutations in phosphodiesterases demonstrated to be one of the causes of autosomal recessive Retinitis Pigmentosa. Phosphodiesterases are important regulators of signal transduction mediated by cyclic GMP and cyclic AMP.

Cyclic GMPs are highly ranked in the compounds results, which can be explained by the elevated levels of retinal cyclic GMP in cases of mutated or downregulated phosphodiesterases. Other compounds related to the disease and to rod cells include: Rolipram, Cilostamide and Sildenafil Citrate, which are selective phosphodiesterase inhibitors.

These results provide novel insight into mechanisms underlying Retinitis Pigmentosa and suggest potential therapeutic approaches such as reducing cyclic GMP levels and/or inducing phosphodiesterase activity. Such approaches may lead to rod cell survival and to improved retinal function in rod cells affected by Retinitis Pigmentosa.

As expected, vitamin A also appears in the compounds list, as a common supplement administered to treat Retinitis Pigmentosa.

This case demonstrated how GeneAnalytics can be used to provide a rapid and simple means of assessing a disease-related gene set and to identify potential therapeutic avenues. GeneAnalytics can help save you time by providing high quality information that facilitates novel discoveries and helps test your hypotheses.

Register now and start analyzing your gene sets at GeneAnalytics.com. Feel free to contact us at [email protected] with any questions you may have. 

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