September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016

Comprehensive Genomewide Functional Characterization of Etiopathogenesis of Primary Congenital Glaucoma for Identification of Potential Therapeutic Agents and Targets.
Author Affiliations & Notes
  • Muneeb A. Faiq
    Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
    Laboratory for Molecular Reproduction and Genetics, All India Institute of Medical Sciences, New Delhi, India
  • Daman Saluja
    Medical Biotechnology Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Centre, University of Delhi, Delhi, India
  • Rima Dada
    Laboratory for Molecular Reproduction and Genetics, All India Institute of Medical Sciences, New Delhi, India
  • Kuldeep Mohanty
    Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
  • Tanuj Dada
    Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
  • Footnotes
    Commercial Relationships   Muneeb Faiq, None; Daman Saluja, None; Rima Dada, None; Kuldeep Mohanty, None; Tanuj Dada, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4799. doi:
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      Muneeb A. Faiq, Daman Saluja, Rima Dada, Kuldeep Mohanty, Tanuj Dada;
      Comprehensive Genomewide Functional Characterization of Etiopathogenesis of Primary Congenital Glaucoma for Identification of Potential Therapeutic Agents and Targets.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4799.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose :
Many genes have been implicated in primary congenital glaucoma (PCG) etiopathogenesis but potential molecular targets and therapeutic agents have not been identified. We did genome wide data mining, interactome identifications, reactome analysis and functional characterization of the genes and pathways involved in etiopathomechanims of PCG.

Methods :
By comprehensive genomewide data mining a list of genes implicated in PCG was prepared and reactome analysis to identify the molecular processes and pathways they are involved in with respect to PCG etiology was carried out. The most imperative gene was identified using Disgenet, Cytoscape, Protein Panther etc. This gene was then cloned and expressed in bacterial expression system. Important mutants (already implicated in PCG) were also cloned and expressed. Functional viabilities of wild type and mutants were compared and analyzed with respect to the assays identified in reactome analysis. Structural modelling of the wild type and mutant gene was also carried out.

Results :
We identified 15 genes (viz. CYP1B1, MYOC, LTBP2, CYP2B6, LTBP3, GLC3B, GLC3C, TYR, FOXC1, MFN2, KIF1B, ADRB2, GLC1C, GLC1B and DUP22Q11.2) to associate with PCG. Pathway analysis revealed that CYP1B1 gene was centrally important. So we selected CYP1B1 for functional characterization. Pathway analysis of CYP1B1 with respect to eye development revealed 36 biochemical processes that may be pivotal in PCG development. Pathway enrichment showed that these 36 processes number down to four major metabolic pathways viz. estradiol, retinoid, arachidonte and melatonin metabolism. The in vitro and in silico characterization of CYP1B1 wild and mutants revealed that all the four processes are impaired by CYP1B1 functional deficit indicating that these four pathways may be involved in various permutations in PCG development. The functional deficit of CYP1B1 was observed to lead to lower production of its metabolic products. Our study identified 28 analytes that may supplement the functional deficit of CYP1B1, thereby, giving a rich repertoire of potential therapeutic agents for PCG.

Conclusions :
This study has found that estradiol, retinoid, arachidonate and melatonin metabolism are important potential targets in PCG therapy. This study has also identified novel therapeutic agents for this disease.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

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