June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Early disease phenotype in canine RPGRORF15 model is characterized by strong up-regulation of pro-inflammatory genes and down-regulation of neuroretinal maintenance genes
Author Affiliations & Notes
  • Tatyana Appelbaum
    Clinical studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, PA
  • William A Beltran
    Clinical studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, PA
  • Evelyn Santana
    Clinical studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, PA
  • Gustavo D Aguirre
    Clinical studies, Univ of Pennsylvania Sch Vet Med, Philadelphia, PA
  • Footnotes
    Commercial Relationships Tatyana Appelbaum, None; William Beltran, None; Evelyn Santana, None; Gustavo Aguirre, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4648. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Tatyana Appelbaum, William A Beltran, Evelyn Santana, Gustavo D Aguirre; Early disease phenotype in canine RPGRORF15 model is characterized by strong up-regulation of pro-inflammatory genes and down-regulation of neuroretinal maintenance genes. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4648.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: Canine X-linked progressive retinal atrophy 1 (XLPRA1) is caused by a 5 nucleotide deletion that introduces a premature stop codon in RPGR exon ORF15, which is also a mutation hotspot in human X-linked retinitis pigmentosa 3 (RP3). The disease shows extensive phenotypic variability in a colony of dogs that all inherited the same RPGR mutation from a single ancestor. In this study, genes associated with photoreceptor protein trafficking and maintenance, were investigated as candidate disease modifiers. Additionally, we examined genes involved in retinal inflammation, apoptosis and innate immune response to determine possible involvement in early stages of the disease.

Methods: Samples from a pedigree derived from XLPRA1 affected male dog outcrossed to unrelated normal mix bred or purebred females were used. Single nucleotide polymorphisms (SNPs) spanning the entire RPGR interacting and protein trafficking genes (RAB8B, RAB8A, RPGRIP1L, WHRN, CEP290, CC2D2A, RAB3IP, MAP9, OPTN, SSX2IP, RAB11B and RP2) were genotyped on the pedigree. RNA from 16 week old normal and XLPRA1 retinas was isolated using a standard TRIzol-based protocol. Retinal gene expression was determined by quantitative RT-PCR for a total of 45 genes, including above 12 genes.

Results: Among 45 genes analyzed, 6 genes (GFAP, TNF, IL6, IL1B, FGF2 and TLR4) were highly up-regulated while 4 genes (CNTFR, PDGFRA, PDGFRB and INSR) were down-regulated in 16 week old XLPRA1 retinas. Three SNPs in intron 1 of RAB8A were the only mutations associated with severe XLPRA1 phenotype (P<0.05). No mutations in other 11 candidate modifier genes were associated with the disease.

Conclusions: We have shown that early stage of canine XLPRA1 is characterized by strong increase in expression of pro-inflammatory cytokines and innate immune response genes as well as by down regulation of some genes responsible for maintenance of retinal cells. This may be the underlying cause of retinal inflammation and photoreceptor apoptosis in advanced form of the disease. In addition, intronic RAB8A mutations can be taken into consideration as putative genetic modifier of the disease phenotype observed in the XLPRA1 pedigree, while RAB8B, RPGRIP1L, WHRN, CEP290, CC2D2A, RAB3IP, MAP9, OPTN, SSX2IP, RAB11B and RP2 genes can be eliminated as candidates.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×