September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Transcriptome and metabolome analysis in patients with retinitis pigmentosa caused by mutations in pre-mRNA splicing factor genes.
Author Affiliations & Notes
  • Sara Balzano
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Andrea Prunotto
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Aurelien Thomas
    Unit of Toxicology, University Center of Legal Medicine, Lausanne, Switzerland
  • Carlo Rivolta
    Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland
  • Footnotes
    Commercial Relationships   Sara Balzano, None; Andrea Prunotto, None; Aurelien Thomas, None; Carlo Rivolta, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 4789. doi:
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      Sara Balzano, Andrea Prunotto, Aurelien Thomas, Carlo Rivolta; Transcriptome and metabolome analysis in patients with retinitis pigmentosa caused by mutations in pre-mRNA splicing factor genes.. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4789.

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

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Abstract

Purpose : Mutations in genes encoding pre-mRNA splicing factors (PRPFs) account for a considerable fraction of dominant retinitis pigmentosa (RP) cases, giving rise to the apparent paradox for which defects in proteins that are ubiquitous and essential for cell survival are in fact causing a tissue-specific and relatively mild phenotype. The purpose of this study is to validate one of the theoretical models for this paradox, represented by the possibility that this specific mutant spliceosomes can selectively affect the maturation of primary transcripts playing an important role in retinal homeostasis.

Methods : We analyzed 14 lymphoblastoid cell lines with various mutations in PRPF31, PRPF3, and PRPF8, as well as 7 controls, for transcriptome-wide RNA expression and we plan to concomitantly perform mass spectrometry-based metabolomic approach to determine associated metabolome dysregulations. For gene expression, we calculated the p-value of a given category related to increasing stringent sets of differentially expressed (DE) genes based on the edgeR significance. Then we ordered the Gene Ontology (GO) categories according to their global significance, i.e. according to the sum of the product of the DE genes significance and the correspondent GO significance. This sum ranged along the variation of the DE genes significance. Everything was done in order to avoid an arbitrary threshold on the DE genes and, thus, an arbitrary definition of the related ontology.

Results : Our data show that the most significant biological process that is dysregulated in cells carrying PRPFs mutations is phagocytosis. Interestingly, previous studies in animal models and human ARPE-19 cells carrying human mutations in the same three PRPF genes have shown impairment in the phagocytic process of photoreceptor outer segments by the retinal pigment epithelium (RPE), a process that, when defective, causes retinal degeneration. Analysis of metabolomics tests are presently underway.

Conclusions : These preliminary results, to be expanded by additional RNA-seq experiments and metabolomics tests, support the notion that the phagocytic process of photoreceptor outer segments by the RPE can be the molecular link between mutations in splicing factor genes and retinal degeneration.

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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