May 2004
Volume 45, Issue 13
ARVO Annual Meeting Abstract  |   May 2004
Changes in BART and ANT–1 in the transgenic model expressing a mutant HRG4(UNC 119) .
Author Affiliations & Notes
  • N. Mori
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • Y. Ishiba
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • S. Kubota
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • A. Kobayashi
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • T. Higashide
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • M. McLaren
    Gray Matter Research, Miami, FL
  • G. Inana
    Ophthalmology, Bscom Palmer Eye Inst, Miami, FL
  • Footnotes
    Commercial Relationships  N. Mori, None; Y. Ishiba, None; S. Kubota, None; A. Kobayashi, None; T. Higashide, None; M. McLaren, None; G. Inana, None.
  • Footnotes
    Support  NIH Grant EY10848,Foundation Fighting Blindness,Research to Prevent Blindness
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 2491. doi:
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      N. Mori, Y. Ishiba, S. Kubota, A. Kobayashi, T. Higashide, M. McLaren, G. Inana; Changes in BART and ANT–1 in the transgenic model expressing a mutant HRG4(UNC 119) . . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2491.

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

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Abstract: : Purpose: HRG4 is a novel photoreceptor protein we have isolated by a differential cloning approach (Higashide et al., J. Biol. Chem. 271:1797–1804,1996). Immunofluorescence microscopy and immunocytochemistry localized HRG4 in the rod and cone photoreceptor synapses, establishing it as the first synaptic protein enriched in the photoreceptors (Higashide et al., Invest Ophthalmol Vis Sci. 39:690–698,1998). A premature termination codon mutation in HRG4 was uncovered in a patient with late–onset cone–rod dystrophy, and transgenic mice expressing the identical mutation developed a late–onset reduction in b–wave by ERG and retinal degeneration with marked synaptic degeneration (A. Kobayashi et al., Invest Ophthalmol Vis Sci. 41:690–698,2000). We have identified and confirmed ARL–2 as the interacting protein for HRG4 by the yeast 2–hybrid strategy (Kobayashi et al., FEBS Letters 534: 26–32, 2003). The mutant truncated HRG4 was shown to bind ARL2 3–fold as much as the wild–type HRG4, most likely sequestering it in a non–functional manner (Mori et al.,ARVO 2003). In the present study, molecular and phenotypic consequences of the increased binding of the mutant truncated HRG4 to ARL2 in the retina was investigated in order to investigate the molecular basis of pathogenicity in the transgenic model. Methods: The status of various proteins related to ARL2 function, including tubulin, BART, ANT–1, and ARL2 itself, was examined in normal and transgenic retinas of different ages by Western blot and immunofluorescence analyses. The status of the transgenic retinas was also examined further by histologic analysis. Results: The level of ARL2 was decreased in the transgenic retinas at 13 and 20 months. The level of BART was increased in older transgenic retinas (>20m), while ANT–1 was decreased in the same transgenics. Some of the older transgenic mice showed a formation of choroidal neovascular membrane (CNV) in the subretinal space. Conclusions: The non–functional sequestering of the important target protein, ARL2, appears to result in eventual decrease of ARL2 in the retina, and disturbances in BART, which binds ARL2, and their target, mitochondrial ANT–1. Since ANT–1 controls the cytoplasmic level of ATP, these changes may result in significant cellular defects leading to retinal degeneration. The older transgenics may be useful for investigation of the mechanism of CNV formation.

Keywords: retinal degenerations: hereditary • proteins encoded by disease genes • choroid: neovascularization 

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