June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Dysregulated expression of POMP and TMEM136 may contribute to impaired proteasome function and endothelial dysfunction in eyes with pseudoexfoliation syndrome/glaucoma
Author Affiliations & Notes
  • Matthias Zenkel
    Department of Ophthalmology, University Erlangen Nuernberg, Erlangen, Germany
  • Ursula Schlotzer-Schrehardt
    Department of Ophthalmology, University Erlangen Nuernberg, Erlangen, Germany
  • Daniel Berner
    Department of Ophthalmology, University Erlangen Nuernberg, Erlangen, Germany
  • Friedrich E Kruse
    Department of Ophthalmology, University Erlangen Nuernberg, Erlangen, Germany
  • André Reis
    Institute of Human Genetics, University Erlangen Nuernberg, Erlangen, Germany
  • Chiea Chuen Khor
    Genome Institute of Singapore, Singapore, Singapore
  • Tin Aung
    Singapore National Eye Center, Singapore, Singapore
  • Francesca Pasutto
    Institute of Human Genetics, University Erlangen Nuernberg, Erlangen, Germany
  • Footnotes
    Commercial Relationships   Matthias Zenkel, None; Ursula Schlotzer-Schrehardt, None; Daniel Berner, None; Friedrich Kruse, None; André Reis, None; Chiea Chuen Khor, None; Tin Aung, None; Francesca Pasutto, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4902. doi:
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      Matthias Zenkel, Ursula Schlotzer-Schrehardt, Daniel Berner, Friedrich E Kruse, André Reis, Chiea Chuen Khor, Tin Aung, Francesca Pasutto; Dysregulated expression of POMP and TMEM136 may contribute to impaired proteasome function and endothelial dysfunction in eyes with pseudoexfoliation syndrome/glaucoma. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4902.

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

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Abstract

Purpose : Recently, a genomewide association study based on a large, international sample collection identified new susceptibility loci for pseudoexfoliation (PEX) syndrome/glaucoma (Aung et al., submitted). To determine the pathophysiological role of the three most significantly associated loci (13q12, 11q23.3, 6p21), we investigated the expression and localization of six associated genes in ocular tissues of PEX and control patients.

Methods : Ocular tissues from 21 donor eyes with PEX and 41 age-matched normal eyes without any known ocular disease (control) were analyzed by qRT-PCR for the expression of fms-related tyrosine kinase 1 (FLT1), proteasome maturation protein (POMP), solute carrier family 46 member 3 (SLC46A3) - [13q12: rs7329408], transmembrane protein 136 (TMEM136), Rho guanine nucleotide exchange factor 12 (ARHGEF12) – [11q23.3: rs11827818], and 1-acylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) – [6p21: rs3130283]. Protein expression levels were analyzed by immunohistochemical and Western blot analyses in 10 PEX and 10 control eyes using antibodies against the 6 genes of interest and lysyl oxidase-like 1 (LOXL1). Tissues were genotyped by TaqMan assays or direct sequencing.

Results : All 6 genes displayed moderate mRNA expression in all ocular tissues analyzed, with highest levels in iris, ciliary body, and retina. For POMP, there was a trend towards reduced expression in the presence of the risk allele of rs7329408. Both mRNA and protein expression of POMP and TMEM136 were significantly reduced by up to 45% (p<0.005) in anterior segment tissues of PEX eyes compared to controls. Immunofluorescence analysis showed POMP, a proteasome maturation protein, to be ubiquitously expressed in most ocular cell types; TMEM136, a transmembrane protein of unknown function, was primarily localized to endothelial cells of blood vessels and aqueous outflow structures. Protein staining intensities were markedly reduced in anterior segment tissues of PEX eyes compared to controls and co-localized to LOXL1-positive PEX material deposits on ocular surfaces and in blood vessel walls.

Conclusions : The newly identified loci provide new biological insights into the pathology of PEX syndrome/glaucoma and highlight a role for impaired proteasome function as well as vascular and trabecular endothelial dysfunction in disease pathogenesis.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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